DNA Damage and Repair

DNA Damage and Repair Mechanisms

Damage to cellular DNA is involved in mutagenesis and the development of cancer. The DNA in a human cell undergoes several thousand to a million damaging events per day, generated by both external (exogenous) and internal metabolic (endogenous) processes. Changes to the cellular genome can generate errors in the transcription of DNA and ensuing translation into proteins necessary for signaling and cellular function. Genomic mutations can also be carried over into daughter generations of cells if the mutation is not repaired prior to mitosis. Once cells lose their ability to effectively repair damaged DNA, there are three possible responses (see Figure 1).

  1. The cell may become senescent, i.e., irreversibly dormant. In 2005, multiple laboratories reported that senescence could occur in cancer cells in vivo as well as in vitro, stopping mitosis and preventing the cell from evolving further.1-4
  2. The cell may become apoptotic. Sufficient DNA damage may trigger an apoptotic signaling cascade, forcing the cell into programmed cell death.
  3. The cell may become malignant, i.e., develop immortal characteristics and begin uncontrolled division.

Figure 1.The pathway of cellular DNA damage and repair that leads to senescence, apoptosis, or cancer

To compensate for the degree and types of DNA damage that occur, cells have developed multiple repair processes including mismatch, base excision, and nucleotide excision repair mechanisms, with little process redundancy. Cells may have evolved to proceed into apoptosis or senescence if overwhelming damage occurs rather than expend energy to effectively repair the damage. The rate at which a cell is able to make repairs is contingent on factors including cell type and cell age.

Sources of DNA Damage

For many years, exogenous sources of damage have been thought to be the primary cause of DNA mutations leading to cancer. However, Jackson and Loeb proposed that endogenous sources of DNA damage also contribute significantly to mutations that lead to malignancy.5 Both environmental and cellular sources can result in similar types of DNA damage.

DNA can be attacked by physical and chemical mutagens. Physical mutagens are primarily radiation sources, including UV (200-300 nm wavelength) radiation from the sun. UV radiation produces covalent bonds that crosslink adjacent pyrimidine (cytosine and thymine) bases in the DNA strand. Ionizing radiation (X-rays) initiates DNA mutations by generating free radicals within the cell that create reactive oxygen species (ROS) and result in single-strand and double-strand breaks in the double helix. Chemical mutagens can attach alkyl groups covalently to DNA bases; nitrogen mustard compounds that can methylate or ethylate the DNA base are examples of DNA alkylating agents. Procarcinogens are chemically inert precursors that are metabolically converted into highly reactive carcinogens. These carcinogens can react with DNA by forming DNA adducts, i.e., chemical entities attached to DNA. Benzo[a]pyrene, a polyaromatic heterocycle, is not itself carcinogenic. It undergoes two sequential oxidation reactions mediated by cytochrome P450 enzymes, which results in benzo[a]pyrenediol epoxide (BPDE), the carcinogenic metabolite that is able to form a covalent DNA adduct (see Figure 2).

Figure 2.Benzo[a]pyrene is oxidized by P450 enzymes to create the highly carcinogenic benzo[a]pyrenediolepoxide.

DNA damage can also result from endogenous metabolic and biochemical reactions, some of which are not well understood.6 Hydrolysis reactions can partially or completely cleave the nucleotide base from the DNA strand. The chemical bond connecting a purine base (adenine or guanine) to the deoxyribosyl phosphate chain can spontaneously break in the process known as depurination. An estimated 10,000 depurination events occur per day in a mammalian cell.7 Depyrimidination (loss of pyrimidine base from thymine or cytosine) also occurs, but at a rate 20 to 100-fold lower than depurination.

Deamination occurs within the cell with the loss of amine groups from adenine, guanine, and cytosine rings, resulting in hypoxanthine, xanthine, and uracil, respectively. DNA repair enzymes are able to recognize and correct these unnatural bases. However, an uncorrected uracil base may be misread as a thymine during subsequent DNA replication and generate a C→T point mutation.

DNA methylation, a specific form of alkylation, occurs within the cell due to a reaction with S-adenosyl methionine (SAM). SAM is an intracellular metabolic intermediate that contains a highly reactive methyl group. In mammalian cells, methylation occurs at the 5-position of the cytosine ring of a cytidine base (C) that is 5’ to a guanosine base (G), i.e., sequence CpG. A significant source of mutation error is the spontaneous deamination of the 5-methylcytosine product of methyl-ation. Loss of the amine group results in a thymine base, which is not detected by DNA repair enzymes as an unnatural base. The resulting substitution is retained in DNA replication, creating a C→T point mutation (see Figure 3).

Figure 3.The 2-phase mutation of cytosine results in thymine, creating a C→T point mutation.

Normal metabolic processes generate reactive oxygen species (ROS), which modify bases by oxidation. Both purine and pyrimidine bases are subject to oxidation. The most common mutation is guanine oxidized to 8-oxo-7,8-dihydroguanine, resulting in the nucleotide 8-oxo-deoxy guano sine (8-oxo-dG). The 8-oxo-dG is capable of base pairing with deoxyadenosine, instead of pairing with deoxycytotidine as expected. If this error is not detected and corrected by mismatch repair enzymes, the DNA subsequently replicated will contain a C→A point mutation. ROS may also cause depurination, depyrimidination, and single-strand or double strand breaks in the DNA.

Other genomic mutations may be introduced during DNA replication in the S phase of the cell cycle. Polymerases that duplicate template DNA have a small but significant error rate, and may incorporate an incorrect nucleotide based on Watson-Crick pairing versus the template DNA. Chemically altered nucleotide precursors may be incorporated into the generated DNA by the polymerase, instead of normal bases. In addition, polymerases are prone to “stuttering” when copying sections of DNA that contain a large number of repeating nucleotides or repeating sequences (microsatellite regions). This enzymatic “stuttering” is due to a strand slippage, when the template and replicated strands of DNA slip out of proper alignment. As a result, the polymerase fails to insert the correct number of nucleotides indicated by the template DNA, resulting in too few or too many nucleotides in the daughter strand.

Single strand and double strand cleavage of the DNA may occur. Single strand breaks may result from damage to the deoxyribose moiety of the DNA deoxyribosylphosphate chain. Breaks also result as an intermediate step of the base excision repair pathway after the removal of deoxyribose phosphate by AP-endonuclease 1.8 When a single strand break occurs, both the nucleotide base and the deoxyribose backbone are lost from the DNA structure. Double strand cleavage most often occurs when the cell is passing through S-phase, as the DNA may be more susceptible to breakage while it is unraveling for use as a template for replication.

Mechanisms of DNA Repair

While the cell is able to evolve into either an apoptotic or senescent state, these actions are performed as a last resort. For each type of DNA damage, the cell has evolved a specific method of repairing the damage or eliminating the damaging compound.

O6-Methylguanine DNA methyltransferase (MGMT; DNA alkyltransferase) cleaves both methyl and ethyl adducts from guanine bases on the DNA structure. The reaction is not a catalytic (enzymatic) reaction but is stoichiometric (chemical), consuming one molecule of MGMT for each adduct removed. Cells that have been engineered to overexpress MGMT are more resistant to cancer, likely because they are able to negate a larger amount of alkylating damage. A recent study by Niture, et al., reports an increase in MGMT expression by use of cysteine/glutathione enhancing drugs and natural antioxidants.9

DNA polymerases such as polymerase-δ contain proofreading activities and are primarily involved in replication error repair. When an error is detected, these polymerases halt the process of DNA replication, work backward to remove nucleotides from the daughter DNA chain until it is apparent that the improper nucleotide is gone, and then reinitiate the forward replication process. Mice with a point mutation in both copies of the Pold1 gene demonstrated a loss of proofreading activity by DNA polymerase-δ and developed epithelial cancers at a significantly higher rate than did mice with wild-type genes or with a single copy mutation.10

A group of proteins known as mismatch excision repair (MMR) enzymes is capable of correcting errors of replication not detected by the proofreading activities of DNA polymerase. MMR enzymes excise an incorrect nucleotide from the daughter DNA and repair the strand using W-C pairing and the parent DNA strand as the correct template.11 This is especially crucial for errors generated during the replication of microsatellite regions, as the proofreading activity of DNA polymerase does not detect these errors. To a lesser degree, MMR enzymes also correct a variety of base pair anomalies resulting from DNA oxidation or alkylation. These mutations include modified base pairs containing O6-methylguanine and 8-oxoguanine, and carcinogen and cisplatin adducts.12,13 Mutations in the human mismatch excision repair genes MSH2 and MLH1 are associated with hereditary non-polyposis colorectal cancer (HNPCC) syndrome.14

Base Excision Repair and Nucleotide Excision Repair

Base excision repair (BER) involves multiple enzymes to excise and replace a single damaged nucleotide base. The base modifications primarily repaired by BER enzymes are those damaged by endogenous oxidation and hydrolysis. A DNA glycosylase cleaves the bond between the nucleotide base and ribose, leaving the ribose phosphate chain of the DNA intact but resulting in an apurinic or apyrimidinic (AP) site. 8-Oxoguanine DNA glycosylase I (Ogg1) removes 7,8-dihydro-8-oxoguanine (8-oxoG), one of the base mutations generated by reactive oxygen species. Polymorphism in the human OGG1 gene is associated with the risk of various cancers such as lung and prostate cancer. Uracil DNA glycosylase, another BER enzyme, excises the uracil that is the product of cytosine deamination, thereby preventing the subsequent C→T point mutation.15 N-Methylpurine DNA glycosylase (MPG) is able to remove a variety of modified purine bases.16

The AP sites in the DNA that result from the action of BER enzymes, as well as those that result from depyrimidination and depurin ation actions, are repaired by the action of AP-endonuclease 1 (APE1). APE1 cleaves the phosphodiester chain 5’ to the AP site. The DNA strand then contains a 3’-hydroxyl group and a 5’-abasic deoxyribose phosphate. DNA polymerase β (Polβ) inserts the correct nucleotide based on the corresponding W-C pairing and removes the deoxyribose phosphate through its associated AP-lyase activity. The presence of X-ray repair cross-complementing group 1 (XRCC1) is necessary to form a heterodimer with DNA ligase III (LIG3). XRCC1 acts as a scaffold protein to present a non-reactive binding site for Polβ, and bring the Polβ and LIG3 enzymes together at the site of repair.17 Poly(ADP-ribose) polymerase (PARP-1) interacts with XRCC1 and Polβ and is a necessary component of the BER pathway.18,19 The final step in the repair is performed by LIG3, which connects the deoxyribose of the replacement nucleotide to the deoxyribosylphosphate backbone. This pathway has been named “short-patch BER”.20

An alternative pathway called “long-patch BER” replaces a strand of nucleotides with a minimum length of 2 nucleotides. Repair lengths of 10 to 12 nucleotides have been reported.21,22 Longpatch BER requires the presence of proliferation cell nuclear antigen (PCNA), which acts as a scaffold protein for the restructuring enzymes.23 Other DNA polymerases, possibly Polδ and Polε, 24 are used to generate an oligonucleotide flap. The existing nucleotide sequence is removed by flap endonuclease-1 (FEN1). The oligonucleotide is then ligated to the DNA by DNA ligase I (LIG1), sealing the break and completing the repair.17 The process used to determine the selection of short-patch versus long patch BER pathways is still under investigation (see Figure 4).25

Figure 4.Schematic of both short-patch and long-patch BER pathways.

While BER may replace multiple nucleotides via the long-patch pathway, the initiating event for both short-patch and long-patch BER is damage to a single nucleotide, resulting in minimal impact on the structure of the DNA double helix. Nucleotide excision repair (NER) repairs damage to a nucleotide strand containing at least 2 bases and creating a structural distortion of the DNA. NER acts to repair single strand breaks in addition to serial damage from exogenous sources such as bulky DNA adducts and UV radiation. 26 The same pathway may be used to repair damage from oxidative stress.27 Over 20 proteins are involved in the NER pathway in mammalian cells, including XPA, XPC-hHR23B, replication protein A (RPA), transcription factor TFIIH, XPB and XPD DNA helicases, ERCC1-XPF and XPG, Polδ, Polε, PCNA, and replication factor C.28 Overexpression of the excision repair cross-complementing (ERCC1) gene has been associated with cisplatin resistance by non-small-cell lung cancer cells29 and corresponds to enhanced DNA repair capacity.30 Global genomic NER (GGR) repairs damage throughout the genome, while a specific NER pathway called Transcription Coupled Repair (TCR) repairs genes during active RNA polymerase transcription.31

Repair of Double-Strand Breaks

Double-strand breaks in DNA can result in loss and rearrangement of genomic sequences. These breaks are repaired by either nonhomologous end-joining (NHEJ) or by homologous recombination (HR), also called recombinational repair or template–assisted repair.

The HR pathway is activated when the cell is in late S/G2 phase and the template has recently been duplicated. This mechanism requires the presence of an identical or nearly identical sequence linked to the damaged DNA region via the centromere for use as a repair template. Double-stranded breaks repaired by this mechanism are usually caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion, resulting in the collapse of the replication fork.

Non-homologous end-joining (NHEJ) is used at other points of the cell cycle when sister chromatids are not available for use as HR templates. When these breaks occur, the cell has not yet replicated the region of DNA that contains the break, so unlike the HR pathway, there is no corresponding template strand available. In NHEJ, the Ku heterodimeric protein positions the two ends of the broken DNA strands for repair without an available template, losing sequence information in the process. Multiple enzymes are involved in the rejoining process, including DNA ligase IV, XRCC4, and DNA-dependent protein kinase (DNA-PK).32,33 NHEJ is inherently mutagenic as it relies on chance pairings, called microhomologies, between the single-stranded tails of the two DNA fragments to be joined (see Figure 5). In higher eukaryotes, DNA-PK is required for NHEJ repair, both via the primary mechanism and via an alternative back-up mechanism (D-NHEJ).34

Figure 5.General mechanism of NHEJ repair of double-strand breaks in DNA.


Future Applications

While DNA damage is a key factor in the development and evolution of cancer cells, continued damage is used as part of clinical treatments for cancer, forcing malignant cells into apoptosis or senescence. Many chemotheraputic drugs such as bleomycin, mitomycin, and cisplatin, are effective because they cause further DNA damage in cancer cells that replicate at a faster rate than surrounding tissue. Cellular DNA repair mechanisms are a doubleedged sword; by reducing mutations that may lead to cancer, these processes strive for genomic integrity, but the same mechanisms in malignant cells allow those cells to survive additional DNA damage and continue uncontrolled growth. In order to block this survival mechanism within cancer cells, clinical trials are now being performed using inhibitors to specific DNA repair enzymes, including MGMT, PARP, and DNA-PK.35-38

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References

Manuel Collado, Jesús Gil, Alejo Efeyan, Carmen Guerra, Alberto J Schuhmacher, Marta Barradas, Alberto Benguría, Angel Zaballos, Juana M Flores, Mariano Barbacid, David Beach, Manuel Serrano
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Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) wa...Read More
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Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2001-06-02
There is increasing evidence that most human cancers contain multiple mutations. By the time a tumor is clinically detectable it may have accumulated tens of thousands of mutations. In normal cells, mutations are rare events occurring at a rate of 10(-10) mutations per nucleotide per cell per generation. We have argued that the ...Read More
Rinne De Bont, Nik van Larebeke
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DNA damage plays a major role in mutagenesis, carcinogenesis and ageing. The vast majority of mutations in human tissues are certainly of endogenous origin. A thorough knowledge of the types and prevalence of endogenous DNA damage is thus essential for an understanding of the interactions of endogenous processes with exogenous a...Read More
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Nucleic Acids Research 2005-01-01
The X-ray repair cross complementing 1 (XRCC1) protein is required for viability and efficient repair of DNA single-strand breaks (SSBs) in rodents. XRCC1-deficient mouse or hamster cells are hypersensitive to DNA damaging agents generating SSBs and display genetic instability after such DNA damage. The presence of certain polym...Read More
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Carcinogenesis 2007-02-01
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which protects the cellular genome and critical oncogenic genes from the mutagenic action of endogenous and exogenous alkylating agents. An expedited elimination of O6-alkylguanines by increasing MGMT activity levels is likely to be a successful chemopreventio...Read More
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Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations through the combined actions of polymerase base selectivity, 3' --> 5' exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine the consequences of defective proofreading in mammals, we created mice with a point mutation ...Read More
W Yang
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Base excision repair (BER) is one of the cellular defense mechanisms repairing damage to nucleoside 5'-monophosphate residues in genomic DNA. This repair pathway is initiated by spontaneous or enzymatic N-glycosidic bond cleavage creating an abasic or apurinic-apyrimidinic (AP) site in double-stranded DNA. Class II AP endonuclea...Read More
Tamara A Ranalli, Samson Tom, Robert A Bambara
Journal of Biological Chemistry 2002-11-01
Base loss is common in cellular DNA, resulting from spontaneous degradation and enzymatic removal of damaged bases. Apurinic/apyrimidinic (AP) endonucleases recognize and cleave abasic (AP) sites during base excision repair (BER). APE1 (REF1, HAP1) is the predominant AP endonuclease in mammalian cells. Here we analyzed the influ...Read More
Ulrike Sattler, Philippe Frit, Bernard Salles, Patrick Calsou
EMBO Reports 2003-04-01
The base excision repair (BER) process removes base damage such as oxidation, alkylation or abasic sites. Two BER sub-pathways have been characterized using in vitro methods, and have been classified according to the length of the repair patch as either 'short-patch' BER (one nucleotide) or 'long-patch' BER (LP-BER; more than on...Read More
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Biochemistry (Washington) 1998-03-17
Mammalian cells possess two distinct pathways for completion of base excision repair (BER): the DNA polymerase beta (Pol beta)-dependent short-patch pathway (replacement of one nucleotide), which is the main route, and the long-patch pathway (resynthesis of 2-6 nucleotides), which is PCNA-dependent. To address the issue of how t...Read More
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EMBO Journal 1997-06-02
Two forms of DNA base excision-repair (BER) have been observed: a 'short-patch' BER pathway involving replacement of one nucleotide and a 'long-patch' BER pathway with gap-filling of several nucleotides. The latter mode of repair has been investigated using human cell-free extracts or purified proteins. Correction of a regular a...Read More
Jung-Suk Sung, Bruce Demple
FEBS Journal 2006-04-01
Base excision DNA repair (BER) is fundamentally important in handling diverse lesions produced as a result of the intrinsic instability of DNA or by various endogenous and exogenous reactive species. Defects in the BER process have been associated with cancer susceptibility and neurodegenerative disorders. BER funnels diverse ba...Read More
A S Balajee, V A Bohr
Gene 2000-05-30
Nucleotide excision repair (NER) is one of the major cellular pathways that removes bulky DNA adducts and helix-distorting lesions. The biological consequences of defective NER in humans include UV-light-induced skin carcinogenesis and extensive neurodegeneration. Understanding the mechanism of the NER process is of great import...Read More
Laurent Gros, Murat K Saparbaev, Jacques Laval
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A number of intrinsic and extrinsic mutagens induce structural damage in cellular DNA. These DNA damages are cytotoxic, miscoding or both and are believed to be at the origin of cell lethality, tissue degeneration, ageing and cancer. In order to counteract immediately the deleterious effects of such lesions, leading to genomic i...Read More
Jin-Sam You, Mu Wang, Suk-Hee Lee
Journal of Biological Chemistry 2003-02-28
XPA, XPC-hHR23B, RPA, and TFIIH all are the damage recognition proteins essential for the early stage of nucleotide excision repair. Nonetheless, it is not clear how these proteins work together at the damaged DNA site. To get insight into the molecular mechanism of damage recognition, we carried out a comprehensive analysis on ...Read More
Rafael Rosell, Miguel Taron, Agusti Barnadas, Giorgio Scagliotti, Carme Sarries, Barbara Roig
Cancer Control 2003-01-01
In spite of the growing list of genetic abnormalities identified as being involved in DNA repair pathways that alter chemosensitivity in non-small-cell lung cancer (NSCLC) patients, translational assays have not yet been developed for use in individualized chemotherapy. In metastatic NSCLC, no single cisplatin-based chemotherapy...Read More
U Vogel, M Dybdahl, G Frentz, B A Nexo
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2000-11-09
We have previously shown that high DNA repair capacity protects psoriasis patients against chemically induced basal cell carcinoma [Dybdahl et al. Mutat. Res. 433 (1999) 15-22]. We have used the same study persons to investigate the correlation between expression of eight genes involved in nucleotide excision repair and DNA repa...Read More
Philip C Hanawalt
Oncogene 2002-12-16
Nucleotide excision repair provides an important cellular defense against a large variety of structurally unrelated DNA alterations. Most of these alterations, if unrepaired, may contribute to mutagenesis, oncogenesis, and developmental abnormalities, as well as cellular lethality. There are two subpathways of nucleotide excisio...Read More
S E Critchlow, S P Jackson
Trends in Biochemical Sciences 1998-10-01
DNA non-homologous end-joining (NHEJ) is a crucial process that has been conserved highly throughout eukaryotic evolution. At its heart is a multiprotein complex containing the KU70-KU80 heterodimer. Recent work has identified additional proteins involved in this pathway, providing insights into the mechanism of NHEJ and reveali...Read More
Huichen Wang, Ange Ronel Perrault, Yoshihiko Takeda, Wei Qin, Hongyan Wang, George Iliakis
Nucleic Acids Research 2003-09-15
Cells of higher eukaryotes process within minutes double strand breaks (DSBs) in their genome using a non-homologous end joining (NHEJ) apparatus that engages DNA-PKcs, Ku, DNA ligase IV, XRCC4 and other as of yet unidentified factors. Although chemical inhibition, or mutation, in any of these factors delays processing, cells ul...Read More
Ronel Perrault, Huichen Wang, Minli Wang, Bustanur Rosidi, George Iliakis
Journal of Cellular Biochemistry 2004-07-01
In cells of higher eukaryotes double strand breaks (DSBs) induced in the DNA after exposure to ionizing radiation (IR) are rapidly rejoined by a pathway of non-homologous end joining (NHEJ) that requires DNA dependent protein kinase (DNA-PK) and is therefore termed here D-NHEJ. When this pathway is chemically or genetically inac...Read More
Isabel Sánchez-Pérez
Clinical & Translational Oncology 2006-09-01
Chemotherapy and radiation are two important modalities for cancer treatment. Many agents in clinical used have the ability to induce DNA damage, however they may be highly cytotoxic as a secondary effect. Different mechanisms are involved both, in detection and repair of DNA damage. The modulation of these pathways, has a great...Read More
Srinivasan Madhusudan, Ian D Hickson
Trends in Molecular Medicine 2005-11-01
Advanced cancer is a leading cause of death in the developed world. Chemotherapy and radiation are the two main treatment modalities currently available. The cytotoxicity of many of these agents is directly related to their propensity to induce DNA damage. However, the ability of cancer cells to recognize this damage and initiat...Read More
Elizabeth Ruth Plummer
Current Opinion in Pharmacology 2006-08-01
Inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) has been extensively investigated in the pre-clinical setting as a strategy for chemo- or radio-potentiation. Recent evidence has suggested that PARP inhibitors might be active as single agents in certain rare inherited cancers that carry DNA repair defec...Read More
Ami Sabharwal, Mark R Middleton
Current Opinion in Pharmacology 2006-08-01
Improving the efficacy of standard chemotherapy by targeting DNA repair mechanisms remains an important area of research. O6-methylguanine-DNA-methyltransferase (MGMT), which repairs alkylating agent damage, is one such target. Downregulation of the gene through epigenetic silencing has been shown to predict response to alkylati...Read More