She states that her DNA expanded from 2 to 12 strands to take up more hydrogen. There is also a belief among people (especially Indians) that the 12 stranded DNA might be the 'kundalini' in the 'mulaadhara' chakra of their body, which when activated supposedly gave the person supernatural powers. In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing.

In Your Spiritual Evolution NOW. And Enjoy inspirational, informational, and spiritual articles sent to you twice monthly. When you sign up you'll get my ebook, Overcoming F-F-Fear Read past issues in the dusty, crusty archives.

'Since having my activation, I feel more at peace, more grounded, more at ease with life in general.' Westminster, CA 'I felt an immediate Spiritual connection, like a huge dark fog had been lifted. I felt a connection to everything around me.' Bosch Al 1450 Dv Manual Transmission.

Cheryl Hartlen Vancouver, B.C., Canada 'Shortly after I had my activation, I started conducting energy healings for my friends. I don't know how I got the idea, Ijust knew how to do it.' Nevada 'I definitely feel more able to view things from higher perspectives. I feel like I am residing from a place of higher perspective instead of just occasionally visiting.'

Florida 'I have had an enormous amount of energy and I feel rejuvenated. I feel very grounded and energetic.' Troy, NY 'This activation is for anyone who is ready to open themselves to their next step - awakening dorment levels of their true essence to its potential.' Seattle, WA 'My food cravings have been diminishing. I am not spending my days secretly bingeing on junk food.'

New York 'Since the activation I feel turbocharged and am always amazed at how much more energy I have.' Tim Steinruck Vancouver, B.C., Canada 'I have a much higher energy level and no longer crave junk food like I had in the past.' The Interdimensional 12 Strand DNA Activation It's time. The energy on the planet is calling for us all to raise our vibration.

After eons of being disconnected from the spiritual portion of your DNA, you can once again experience being your Divine Self. Step up to the next level of your spiritual evolution with the activation of your 12 DNA strands, the 12 layers of interdimensional energy that surround them, and your Akashic Record. ' For those who carry the activated DNA, love will lead. For those who are still undergoing the changeover, love will be easier to attain.

For those who have yet to awaken, fear will be amplified until a higher way is entertained.' Seven Sisters from Lauren Gorgo About Your DNA. As scientific research has now proven, our DNA, shown on this page in the familiar double helix configuration, holds the genetic codes for your physical and emotional evolution. Still to be discovered by science is the fact that your DNA has a much greater purpose than simply being a blueprint for your body. The Genome Project decoded approximately 3% of the total physical DNA.

The remaining 97% was then termed 'junk', inferring it has no purpose. The truth is that the human body is extremely efficient and anything that is of no use becomes atrophied and is evolved out of existence within a few generations. If 97% of our DNA is junk, why do we still have it? That so-called 'junk DNA' in your body contains all your history since you first incarnated onto this planet, many lifetimes ago. It's where your akashic record, the record of your Soul, resides. Our DNA has been called a living library because of the wealth of information stored on it. 'Hard to believe, but lurking in your DNA are many energies that are quantum.

They're interdimensional attributes of biology clearly given to you by the Pleiadians over 50,000 years ago.' There are ten additional strands of DNA, or five double helix strands, which were eons ago. Science has yet to discover these strands, although they have seen the shadows of them on their electronic microscopes. They call them 'shadow DNA'.

With The Interdimensional 12 Strand DNA Activation, you have access to ten times the information available from your DNA. These additional strands encompass the following areas of your life: • Connection to God/Spirit • Inner vision, receiving messages from spiritual guidance • Communication, both physical and spiritual • Love, both human and Divine • Physical Body • Life force energy (Chi) and personal will What makes The Interdimensional 12 Strand DNA Activation so unique? The Interdimensional 12 Strand DNA Activation, as it was given to me by my spirit guides, is unlike any other on the planet. What makes it so different from all the other DNA activations? • It activates the 12 interdimensional layers of energy that surround the DNA, connecting you to the 12 dimensions that are accessible to us now at this point in our evolution. • You participate in the activation, experiencing the energy of it and making it more powerful.

You'll be gently and carefully guided through the process by me and I'll be connected to your energetically to ensure that your activation is successful. • The Interdimensional 12 Strand DNA Activation utilizes color and sound.

The vibrations of the sacred open the receptors of your cells, allowing the activation to more easily be imprinted on the DNA. Sound sets the vibration of the body at the correct rate to receive the activation at each level. The energy vibration of colors adds to the power of this activation. The benefits of this activation (the purple text is verbatim from my spirit guides) are: • Thirst for clean water. The new intracellular electromagnetic connections in your body will naturally encourage you to drink more pure water. This results in a more pure body, free of toxins.

Your body will be working with a greater number of electromagnetic connections and needs to be properly hydrated to ensure clear, strong communication between you and your spirit guides. • Hunger for pure food. Your cravings for food will change effortlessly to that which is more pure and has a greater nutritional content, such as organic and raw foods. This process will be effortless, almost seeming to be automatic. • Greater health. You'll have a clearer, stronger connection to your body and will be able to communicate with and reprogram the DNA in every cell. Additionally, as you shift your eating and drinking habits to include healthier choices, your body will respond by having better health.

• Inner peace. • Greater energy. The increased number of electromagnetic connections within your body will enhance the natural flow of energy throughout all your physical systems.

• More clear connection to God/spiritual guidance. The activation of the 12 DNA strands is a reconnection to your true Divine Self. • Connection to all living things - animals, devas, nature spirits, and Gaia herself. • Connection to other dimensions. You'll be able to connect more easily to higher dimensions for spiritual wisdom. You are a multidimensional being, residing in many dimensions other than this, the third dimension.

What you call your Higher Self is often you, in another dimension. The Interdimensional 12 Strand DNA Activation is a brief and powerful process that begins with a meditational breathing exercise to center you and bring you into a relaxed yet focused meditational state.

The DNA activation process is similar to a guided visualization or meditation. It includes the activation of all 12 strands of your DNA plus the activation of the 12 interdimensional layers of energy that surround the DNA.

The Interdimensional 12 Strand DNA Activation takes approximately one hour, including pre-instructions, the activation, and discussion afterward. The activation can be done by phone or remotely using a specially selected crystal as a surrogate for you. Have the Interdimensional 12 Strand DNA Activation your way!

It's available in CD and mp3 download: Interdimensional 12 Strand DNA Activation mp3 Download $24.95 USD. To insure that your Interdimensional 12 strand DNA activation will be most effective. Should you repeat the Interdimensional 12 Strand DNA Activation? For information about repeat DNA activations. Once you've had the Interdimensional 12 Strand DNA Activation, all will be more powerful and effective for you. For more information about the de-activation of our 12 DNA strands, consult these books: by Zacheria Sitchen - Kryon book 11 written by Lee Carroll - Kryon book 10 written by Lee Carroll by Barbara Hand Clow by Barbara Marciniak by Barbara Marciniak by Barbara Marciniak by Barbara Marciniak.. Kathy Wilson 680 Rainier Lane, Port Ludlow, WA 98365 Phone: 360.437.9328 Email All material on this website ©2009 If you see something you would like to use, please ask.

More than likely I'd be happy to share it, and I would like you to honor my work by allowing me to give it to you..

DNA damage resulting in multiple broken chromosomes DNA repair is a collection of processes by which a identifies and corrects damage to the molecules that encode its. In human cells, both normal activities and environmental factors such as can cause DNA damage, resulting in as many as 1 individual per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to the that the affected DNA encodes. Other lesions induce potentially harmful in the cell's genome, which affect the survival of its daughter cells after it undergoes. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs).

This can eventually lead to malignant tumors, or as per the. The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states: • an irreversible state of dormancy, known as • cell suicide, also known as or • unregulated cell division, which can lead to the formation of a that is The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence have turned out to be involved in DNA damage repair and protection. Further information: and DNA damage, due to environmental factors and normal processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as ) can impede a cell's ability to carry out its function and appreciably increase the likelihood of formation and contribute to.

The vast majority of DNA damage affects the of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike and, DNA usually lacks and therefore damage or disturbance does not occur at that level. DNA is, however, and wound around 'packaging' proteins called (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage. Sources of damage [ ] DNA damage can be subdivided into two main types: • damage such as attack by produced from normal metabolic byproducts (spontaneous mutation), especially the process of • also includes • exogenous damage caused by external agents such as • ultraviolet [UV 200–400 ] from the sun • other radiation frequencies, including and • or thermal disruption • certain • human-made, especially compounds that act as DNA • The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a, for example, through ).

Types of damage [ ] There are several types of damage to DNA due to endogenous cellular processes: • of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species, • of bases (usually ), such as formation of, 1-methyladenine, • of bases, such as,, and depyrimidination.

• (i.e., benzo[a]pyrene diol epoxide-dG adduct, aristolactam I-dA adduct) • mismatch of bases, due to errors in, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted. • Monoadduct damage cause by change in single nitrogenous base of DNA • Diadduct damage Damage caused by exogenous agents comes in many forms. Some examples are: • causes crosslinking between adjacent cytosine and thymine bases creating.

This is called. • creates mostly free radicals. The damage caused by free radicals is called. • such as that created by radioactive decay or in causes breaks in DNA strands. Intermediate-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.

• Thermal disruption at elevated temperature increases the rate of (loss of bases from the DNA backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the, which grow in at 40–80 °C. The rate of depurination (300 residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an response cannot be ruled out.

• Industrial chemicals such as and, and environmental chemicals such as found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and, just to name a few. UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar and tautomeric shift. Nuclear versus mitochondrial DNA damage [ ] In human cells, and cells in general, DNA is found in two cellular locations — inside the and inside the.

Nuclear DNA (nDNA) exists as during non-replicative stages of the and is condensed into aggregate structures known as during. In either state the DNA is highly compacted and wound up around bead-like proteins called. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, (ROS), or, byproducts of the constant production of (ATP) via, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is, which is present in both the mitochondria and of eukaryotic cells.

Senescence and apoptosis [ ] Senescence, an irreversible process in which the cell no longer, is a protective response to the shortening of the. The telomeres are long regions of repetitive that cap chromosomes and undergo partial degradation each time a cell undergoes division (see ). In contrast, is a reversible state of cellular dormancy that is unrelated to genome damage (see ).

Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism, which serves as a 'last resort' mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth. Unregulated cell division can lead to the formation of a tumor (see ), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer. DNA damage and mutation [ ] It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damage and mutation are fundamentally different. Damage results in physical abnormalities in the DNA, such as single- and double-strand breaks, residues, and polycyclic aromatic hydrocarbon adducts.

DNA damage can be recognized by enzymes, and thus can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and thus translation into a protein will also be blocked. Replication may also be blocked or the cell may die. In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired.

At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damage and mutation are related because DNA damage often causes errors of DNA synthesis during replication or repair; these errors are a major source of mutation.

Given these properties of DNA damage and mutation, it can be seen that DNA damage is a special problem in non-dividing or slowly-dividing cells, where unrepaired damage will tend to accumulate over time. On the other hand, in rapidly-dividing cells, unrepaired DNA damage that does not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival.

Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus, DNA damage in frequently dividing cells, because it gives rise to mutations, is a prominent cause of cancer. In contrast, DNA damage in infrequently-dividing cells is likely a prominent cause of aging.

DNA repair mechanisms [ ] Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the (but cells remain superficially functional when non-essential genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort. Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place. Direct reversal [ ] Cells are known to eliminate three types of damage to their DNA by chemically reversing it.

These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone.

The formation of upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The process directly reverses this damage by the action of the enzyme, whose activation is obligately dependent on energy absorbed from (300–500 nm ) to promote catalysis. Photolyase, an old enzyme present in,, and most no longer functions in humans, who instead use to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is rather than. A generalized response to methylating agents in bacteria is known as the and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes. The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.

Single-strand damage [ ]. Structure of the base-excision repair enzyme excising a hydrolytically-produced uracil residue from DNA.

The uracil residue is shown in yellow. When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand. • (BER) repairs damage to a single by deploying enzymes called. These enzymes remove a single nitrogenous base to create an apurinic or apyrimidinic site (). Enzymes called nick the damaged DNA backbone at the AP site.

DNA polymerase then removes the damaged region using its 5’ to 3’ exonuclease activity and correctly synthesizes the new strand using the complementary strand as a template. • (NER) repairs damaged DNA which commonly consists of bulky, helix-distorting damage, such as caused by UV light. Damaged regions are removed in 12–24 nucleotide-long strands in a three-step process which consists of recognition of damage, excision of damaged DNA both upstream and downstream of damage by, and resynthesis of removed DNA region. NER is a highly evolutionarily conserved repair mechanism and is used in nearly all eukaryotic and prokaryotic cells. In prokaryotes, NER is mediated.

In eukaryotes, many more proteins are involved, although the general strategy is the same. • systems are present in essentially all cells to correct errors that are not corrected. These systems consist of at least two proteins. One detects the mismatch, and the other recruits an endonuclease that cleaves the newly synthesized DNA strand close to the region of damage. Coli, the proteins involved are the Mut class proteins.

This is followed by removal of damaged region by an exonuclease, resynthesis by DNA polymerase, and nick sealing by DNA ligase. Double-strand breaks [ ] Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Noted that double-strand breaks and a 'cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate.' Three mechanisms exist to repair double-strand breaks (DSBs): (NHEJ), (MMEJ), and. In an in vitro system, MMEJ occurred in mammalian cells at the levels of 10–20% of HR when both HR and NHEJ mechanisms were also available.

DNA ligase, shown above repairing chromosomal damage, is an enzyme that joins broken nucleotides together by catalyzing the formation of an internucleotide bond between the phosphate backbone and the deoxyribose nucleotides. In NHEJ,, a specialized that forms a complex with the cofactor, directly joins the two ends. To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate. NHEJ can also introduce mutations during repair.

Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are 'backup' NHEJ pathways in higher. Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during, the process that generates diversity in and in the. Homologous recombination requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for during meiosis.

This pathway allows a damaged chromosome to be repaired using a sister (available in G2 after DNA replication) or a as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the and are typically repaired by recombination. MMEJ starts with short-range end resection by nuclease on either side of a double-strand break to reveal microhomology regions. In further steps, (PARP1) is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of (FEN1) to remove overhanging flaps. This is followed by recruitment of – to the site for ligating the DNA ends, leading to an intact DNA. MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.

The has a remarkable ability to survive DNA damage from and other sources. At least two copies of the genome, with random DNA breaks, can form DNA fragments through. Partially overlapping fragments are then used for synthesis of regions through a moving that can continue extension until they find complementary partner strands. In the final step there is by means of -dependent. Introduce both single- and double-strand breaks in the course of changing the DNA's state of, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.

Translesion synthesis [ ] Translesion synthesis (TLS) is a DNA damage tolerance process that allows the machinery to replicate past DNA lesions such as. It involves switching out regular for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication factor. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, mediates error-free bypass of lesions induced by, whereas introduces mutations at these sites.

Pol η is known to add the first adenine across the using and the second adenine will be added in its syn conformation using. From a cellular perspective, risking the introduction of during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized either bypassing or repairing lesions at locations of stalled DNA replication.

For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although can cause targeted and semi-targeted mutations. Paromita Raychaudhury and Ashis Basu studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. Coli with specific DNA polymerase knockouts.

Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases. A bypass platform is provided to these polymerases by (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of, PCNA is ubiquitinated, or modified, by the RAD6/ to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication.

After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol η, yet if TLS results in a mismatch, a specialized polymerase is needed to extend it;. Pol ζ is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol ι to fix the lesion, then PCNA may switch to Pol ζ to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication. Global response to DNA damage [ ] Cells exposed to, or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks.

Moreover, DNA damaging agents can damage other such as,,, and. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the, are among known stimulation signals for a global response to DNA damage. The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance,. The common features of global response are induction of multiple, arrest, and inhibition of. Initial steps [ ] The packaging of eukaryotic DNA into presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow DNA repair, the chromatin must be.

In eukaryotes, dependent complexes and are two predominant factors employed to accomplish this remodeling process. Chromatin relaxation occurs rapidly at the site of a DNA damage. In one of the earliest steps, the stress-activated protein kinase,, phosphorylates on serine 10 in response to double-strand breaks or other DNA damage. This facilitates the mobilization of SIRT6 to DNA damage sites, and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs.

Protein starts to appear at DNA damage sites in less than a second, with half maximum accumulation within 1.6 seconds after the damage occurs. PARP1 synthesizes (poly (ADP-ribose) or PAR) chains on itself. Next the chromatin remodeler quickly attaches to the product of PARP1 action, a poly-ADP ribose chain, and ALC1 completes arrival at the DNA damage within 10 seconds of the occurrence of the damage. About half of the maximum chromatin relaxation, presumably due to action of ALC1, occurs by 10 seconds. This then allows recruitment of the DNA repair enzyme, to initiate DNA repair, within 13 seconds.

ΓH2AX, the phosphorylated form of is also involved in the early steps leading to chromatin decondensation after DNA double-strand breaks. The variant H2AX constitutes about 10% of the H2A histones in human chromatin. ΓH2AX (H2AX phosphorylated on serine 139) can be detected as soon as 20 seconds after irradiation of cells (with DNA double-strand break formation), and half maximum accumulation of γH2AX occurs in one minute.

The extent of chromatin with phosphorylated γH2AX is about two million base pairs at the site of a DNA double-strand break. ΓH2AX does not, itself, cause chromatin decondensation, but within 30 seconds of irradiation, protein can be detected in association with γH2AX. RNF8 mediates extensive chromatin decondensation, through its subsequent interaction with, a component of the nucleosome remodeling and deacetylase complex. Occurs in a heterodimeric complex with. This complex further complexes with the protein and with. This larger complex rapidly associates with UV-induced damage within chromatin, with half-maximum association completed in 40 seconds.

The PARP1 protein, attached to both DDB1 and DDB2, then (creates a poly-ADP ribose chain) on DDB2 that attracts the DNA remodeling protein. Action of ALC1 relaxes the chromatin at the site of UV damage to DNA. This relaxation allows other proteins in the pathway to enter the chromatin and repair UV-induced damages. After rapid, are activated to allow DNA repair to occur before the cell cycle progresses. First, two, and are activated within 5 or 6 minutes after DNA is damaged.

This is followed by phosphorylation of the cell cycle checkpoint protein, initiating its function, about 10 minutes after DNA is damaged. DNA damage checkpoints [ ] After DNA damage, are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. Occur at the / and / boundaries.

An intra- checkpoint also exists. Checkpoint activation is controlled by two master, and. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled. These kinases downstream targets in a cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including,, and has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins. DNA damage checkpoint is a that blocks progression in G1, G2 and and slows down the rate of S phase progression when is damaged.

It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide. Checkpoint Proteins can be separated into four groups: (PI3K)-like, (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM () and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled. An important downstream target of ATM and ATR is, as it is required for inducing following DNA damage. The is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating / complexes.

The prokaryotic SOS response [ ] The is the changes in in and other bacteria in response to extensive DNA damage. The SOS system is regulated by two key proteins: and.

The LexA is a that binds to sequences commonly referred to as SOS boxes. In it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes. The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the. The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled or double-strand breaks, which are processed by to separate the two DNA strands. In the initiation step, RecA protein binds to ssDNA in an driven reaction creating RecA–ssDNA filaments.

RecA–ssDNA filaments activate LexA auto activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.

In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome.

The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD'2 (also called DNA polymerase V), are induced later on as a last resort. Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene expression. Eukaryotic transcriptional responses to DNA damage [ ] cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, control, protein trafficking and degradation.

Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the of cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage. In general global response to DNA damage involves expression of multiple genes responsible for, homologous recombination, nucleotide excision repair,, global transcriptional activation, genes controlling mRNA decay, and many others.

A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of [Y family translesion DNA present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes. DNA repair and aging [ ]. DNA repair rate is an important determinant of cell pathology Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get and infections more often, and, as a consequence, have shorter lifespans than wild-type mice. In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.

However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation. If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis, or cancer.

Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens, and correspondingly increased cancer risk (see ). On the other hand, organisms with enhanced DNA repair systems, such as, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand break-inducing effects of, likely due to enhanced efficiency of DNA repair and especially NHEJ.

Longevity and caloric restriction [ ]. Most life span influencing genes affect the rate of DNA damage A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organism's diet. Reproducibly results in extended lifespan in a variety of organisms, likely via pathways and decreased. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.

Several agents reported to have anti-aging properties have been shown to attenuate constitutive level of signaling, an evidence of reduction of, and concurrently to reduce constitutive level of ] induced by endogenously generated reactive oxygen species. For example, increasing the of the gene SIR-2, which regulates DNA packaging in the nematode worm, can significantly extend lifespan. The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction. Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents, although similar effects have not been observed in mitochondrial DNA. Elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.

This observation supports the theory of the, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life. Medicine and DNA repair modulation [ ]. Main article: Hereditary DNA repair disorders [ ] Defects in the NER mechanism are responsible for several genetic disorders, including: •: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging •: hypersensitivity to UV and chemical agents •: sensitive skin, brittle hair and nails Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.

Other DNA repair disorders include: •: premature aging and retarded growth •: sunlight hypersensitivity, high incidence of (especially ). •: sensitivity to ionizing radiation and some chemical agents All of the above diseases are often called 'segmental ' (') because their victims appear elderly and suffer from aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age. Other diseases associated with reduced DNA repair function include, hereditary and hereditary. DNA repair and cancer [ ] Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. There are at least 34.

Many of these mutations cause DNA repair to be less effective than normal. In particular, (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. And, two famous genes whose mutations confer a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination. Cancer therapy procedures such as and work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing — most typically cancer cells — are preferentially affected.

The side-effect is that other non-cancerous but rapidly dividing cells such as progenitor cells in the gut, skin, and hematopoietic system are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).; in the context of therapies targeting DNA damage response genes, the latter approach has been termed ‘synthetic lethality’. Perhaps the most well-known of these 'synthetic lethality' drugs is the poly(ADP-ribose) polymerase 1 () inhibitor, which was approved by the Food and Drug Administration in 2015 for the treatment in women of BRCA-defective ovarian cancer. Tumor cells with partial loss of DNA damage response (specifically, repair) are dependent on another mechanism – single-strand break repair – which is a mechanism consisting, in part, of the PARP1 gene product. Is combined with chemotherapeutics to inhibit single-strand break repair induced by DNA damage caused by the co-administered chemotherapy. Tumor cells relying on this residual DNA repair mechanism are unable to repair the damage and hence are not able to survive and proliferate, whereas normal cells can repair the damage with the functioning homologous recombination mechanism. Many other drugs for use against other residual DNA repair mechanisms commonly found in cancer are currently under investigation.

However, synthetic lethality therapeutic approaches have been questioned due to emerging evidence of acquired resistance, achieved through rewiring of DNA damage response pathways and reversion of previously-inhibited defects. DNA repair defects in cancer [ ] It has become apparent over the past several years that the DNA damage response acts as a barrier to the malignant transformation of preneoplastic cells.

Previous studies have shown an elevated DNA damage response in cell-culture models with oncogene activation and preneoplastic colon adenomas. DNA damage response mechanisms trigger cell-cycle arrest, and attempt to repair DNA lesions or promote cell death/senescence if repair is not possible. Replication stress is observed in preneoplastic cells due to increased proliferation signals from oncogenic mutations. Replication stress is characterized by: increased replication initiation/origin firing; increased transcription and collisions of transcription-replication complexes; nucleotide deficiency; increase in reactive oxygen species (ROS). Replication stress, along with the selection for inactivating mutations in DNA damage response genes in the evolution of the tumor, leads to downregulation and/or loss of some DNA damage response mechanisms, and hence loss of DNA repair and/or senescence/programmed cell death. In experimental mouse models, loss of DNA damage response-mediated cell senescence was observed after using a (shRNA) to inhibit the double-strand break response kinase ataxia telangiectasia (), leading to increased tumor size and invasiveness. Humans born with inherited defects in DNA repair mechanisms (for example, ) have a higher cancer risk.

The prevalence of DNA damage response mutations differs across cancer types; for example, 30% of breast invasive carcinomas have mutations in genes involved in homologous recombination. In cancer, downregulation is observed across all DNA damage response mechanisms (base excision repair (BER), nucleotide excision repair (NER), DNA mismatch repair (MMR), homologous recombination repair (HR), non-homologous end joining (NHEJ) and translesion DNA synthesis (TLS).

As well as mutations to DNA damage repair genes, mutations also arise in the genes responsible for arresting the to allow sufficient time for DNA repair to occur, and some genes are involved in both DNA damage repair and cell cycle checkpoint control, for example ATM and checkpoint kinase 2 (CHEK2) – a tumor suppressor that is often absent or downregulated in non-small cell lung cancer. A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error prone microhomology-mediated end joining pathway with increased expression in various cancers. Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes.

For example, when 113 colorectal cancers were examined in sequence, only four had a in the DNA repair gene, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region. Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the,, which down-regulates MLH1. In further examples (tabulated in Table 4 of this reference ), epigenetic defects were found at frequencies of between 13%–100% for the DNA repair genes,,,,,,,,,, and. These epigenetic defects occurred in various cancers (e.g.

Breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.

Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two review articles, and two broad experimental survey articles also document most of these epigenetic DNA repair deficiencies in cancers.

Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see ) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to. The two gray-highlighted genes and, are required for repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers.

As indicated in the Wikipedia articles on and, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see ) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself. Cyan-highlighted genes are in the (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks.

In MMEJ repair of a double-strand break, an homology of 5–25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix.

MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway., the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung. PARP1 is also over-expressed when its promoter region site is hypomethylated, and this contributes to progression to endometrial cancer, BRCA-mutated ovarian cancer, and BRCA-mutated serous ovarian cancer. Cebora K810 Mig Manual Treadmill. Other genes in the pathway are also over-expressed in a number of cancers (see for summary), and are also shown in cyan. Genome-wide distribution of DNA repair in human somatic cells [ ] Differential activity of DNA repair pathways across various regions of the human genome causes mutations to be very unevenly distributed within tumor genomes. In particular, the gene-rich, early-replicating regions of the human genome exhibit lower mutation frequencies than the gene-poor, late-replicating. One mechanism underlying this involves the, which can recruit proteins, thereby lowering mutation rates in -marked regions.

Another important mechanism concerns, which can be recruited by the transcription machinery, lowering somatic mutation rates in active genes and other open chromatin regions. DNA repair and evolution [ ] The basic processes of DNA repair are highly among both and and even among ( which infect ); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms. The ability of a large number of protein to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see. The indicates that single-cell life began to proliferate on the planet at some point during the period, although exactly when recognizably modern life first emerged is unclear. Became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the ') due to organisms, as well as the presence of potentially damaging in the cell due to, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced.

Rate of evolutionary change [ ] On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, may propagate into the genomes of the cell's progeny. Should such an event occur in a cell that will eventually produce a, the mutation has the potential to be passed on to the organism's offspring. The rate of in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change. DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities.

The tension between evolvability and mutation repair and protection needs further investigation. DNA repair technology [ ] A technology named clustered regularly interspaced short palindromic repeat shortened to -Cas9 was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision. It is a cheaper, more efficient and precise than other technologies.

With the help of CRISPR–Cas9,parts of a genome can be edited by scientists by removing or adding or altering parts in a DNA sequence. See also [ ].