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Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.
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Molecular Cell Biology. 4th edition.
Lodish H, Berk A, Zipursky SL, et al.
New York: W. H. Freeman; 2000.
Section 12.4DNA Damage and Repair and Their Role in Carcinogenesis
The DNA sequence can be changed as the result of copying errors introduced by DNA polymerases during replication and by environmental agents such as mutagenic chemicals and certain types of radiation. If DNA sequence changes, whatever their cause, are left uncorrected, both growing and nongrowing somatic cells might accumulate so many mutations that they could no longer function. In addition, the DNA in germ cells might incur too many mutations for viable offspring to be formed. Thus the correction of DNA sequence errors in all types of cells is important for survival.
The relevance of DNA damage and repair to the generation of cancer (carcinogenesis) became evident when it was recognized that all agents that cause cancer (carcinogens) also cause a change in the DNA sequence and thus are mutagens. All the effects of carcinogenic chemicals on tumor production can be accounted for by the DNA damage that they cause and by the errors introduced into DNA during the cells' efforts to repair this damage. Likewise, ultraviolet (UV) radiation and ionizing radiation (x-rays and atomic particles) not only modify DNA, but also can cause cancer in animals and can transform normal cells in culture into rapidly proliferating, cancer-type cells. The ability of ionizing radiation to cause human cancer, especially leukemia, was dramatically shown by the increased rates of leukemia among survivors of the atomic bombs dropped in World War II, and more recently by the increase in melanoma (skin cancer) in individuals exposed to too much sunlight.
Table 12-2 lists the general types of DNA damage and their causes. In this section, we first describe the very efficient mechanism whereby cells correct copying errors and then examine how various chemical carcinogens cause damage to DNA. Finally, we consider several cellular mechanisms for repairing chemical- or radiation-damaged DNA. The role of these DNA-repair systems in carcinogenesis is introduced here and discussed in more detail in Chapter 24.
DNA Lesions That Require Repair.
Proofreading by DNA Polymerase Corrects Copying Errors
Because the specificity of nucleotide addition by DNA polymerases is determined by Watson-Crick base pairing, a wrong base (e.g., A instead of G) occasionally is inserted during DNA synthesis. Indeed, the α subunit of E. coli DNA polymerase III introduces about 1 incorrect base in 104 internucleotide linkages during replication in vitro. Since an average E. coli gene is about 103 bases long, an error frequency of 1 in 104 base pairs would cause a potentially harmful mutation in every tenth gene during each replication, or 10−1 mutations per gene per generation. However, the measured mutation rate in bacterial cells is much less, about 1 mistake in 109 nucleotide polymerization events or, equivalently, 10−5 to 10−6 mutations per gene per generation (assuming ≈1000 base pairs per gene).
This increased accuracy in vivo is largely due to the proofreading function of E. coli DNA polymerases. Figure 12-20 depicts an experiment demonstrating that the 3′ → 5′ exonuclease activity of E. coli DNA polymerase I can remove a mismatched base at the 3′ growing end of a synthetic primer-template complex. In DNA polymerase III, this function resides in the ϵ subunit of the core polymerase. When an incorrect base is incorporated during DNA synthesis, the polymerase pauses, then transfers the 3′ end of the growing chain to the exonuclease site where the mispaired base is removed. Then the 3′ end is transferred back to the polymerase site, where this region is copied correctly (Figure 12-21). Proofreading is a property of almost all bacterial DNA polymerases. Both the δ and ϵ DNA polymerases of animal cells, but not the α polymerase, also have proofreading activity. It seems likely that this function is indispensable for all cells to avoid excessive genetic damage.
Figure 12-20
Experimental demonstration of the proofreading function of E. coli DNA polymerase I. An artificial template [poly(dA)] and a corresponding primer end-labeled with [3H]thymidine residues were constructed. An "incorrect" cytidine labeled (more...)
Schematic model of the proofreading function of DNA polymerases. All DNA polymerases have a similar three-dimensional structure, which resembles a half-opened right hand. The "fingers" bind the single-stranded segment of the template, (more...)
Genetic studies in E. coli have shown that proofreading does, indeed, play a critical role in maintaining sequence fidelity during replication. Mutations in the gene encoding the ϵ subunit of DNA polymerase III inactivate the proofreading function and lead to a thousandfold increase in the rate of spontaneous mutations. E. coli possesses an additional mechanism for checking the fidelity of DNA replication by identifying mispaired bases in newly replicated DNA. This mismatch-repair machinery, discussed later, determines which strand is to be repaired by distinguishing the newly replicated strand (the one in which an error occurred during replication) from the template strand.
Chemical Carcinogens React with DNA Directly or after Activation
Chemicals, which are thought to be the cause of many human cancers, were originally associated with cancer through experimental studies in animals. The classic experiment is to repeatedly paint a test substance on the back of a mouse and look for development of both local and systemic tumors in the animal. Although the many substances identified as chemical carcinogens have a very broad range of structures with no obvious unifying features, they can be classified into two broad categories: direct-acting and indirect-acting (Figure 12-22).
Structures of some chemical carcinogens. Direct-acting carcinogens are highly electrophilic compounds that can react with DNA. Indirect-acting carcinogens must be metabolized before they can react with DNA. All these chemicals act as mutagens.
Direct-acting carcinogens, of which there are only a few, are reactive electrophiles (compounds that seek out and react with negatively charged centers in other compounds). By chemically reacting with nitrogen and oxygen atoms in DNA, these compounds modify certain nucleotides so as to distort the normal pattern of base pairing. If these modified nucleotides were not repaired, they would allow an incorrect nucleotide to be incorporated during replication. Figure 8-6 shows how one chemical carcinogen, ethyl methanesulfonate (EMS), causes mutations.
Indirect-acting carcinogens generally are unreactive, water-insoluble compounds. They can act as potent cancer inducers only after conversion to ultimate carcinogens by introduction of electrophilic centers. Such metabolic activation of carcinogens is carried out by enzymes that are normal body constituents. In animals, activation of indirect-acting carcinogens often is carried out by liver enzymes that normally function to detoxify noxious chemicals (e.g., therapeutic drugs, insecticides, polycyclic hydrocarbons, and some natural products). Many of these compounds are so fat-soluble that they would accumulate continually in fat cells and lipid membranes and not be excreted from the body. The detoxification system works by converting such compounds to water-soluble derivatives, which the body can excrete.
Detoxification begins with a powerful series of oxidation reactions catalyzed by a set of proteins called cytochrome P-450. These enzymes, which are bound to endoplasmic reticulum membranes, can oxidize even highly unreactive compounds such as polycyclic aromatic hydrocarbons. Oxidation of polycyclic aromatics produces an epoxide, a very reactive electrophilic group:
Usually these epoxides are rapidly hydrolyzed into hydroxyl groups, which are then coupled to glucuronic acid or other groups, producing compounds soluble enough in water to be excreted. Some intermediate epoxides, however, are only slowly hydrolyzed to hydroxyl groups, probably because the relevant enzyme (epoxide hydratase) cannot get to the epoxide to act on it. For example, the indirect-acting carcinogen benzo(a)pyrene, shown in Figure 12-22, undergoes two epoxidation reactions to yield a highly reactive electrophilic ultimate carcinogen:
Other types of indirect-acting carcinogens are activated by different oxidative pathways, which also involve P-450 enzymes.
The Carcinogenic Effect of Chemicals Correlates with Their Mutagenicity
As noted earlier, all chemical carcinogens act as mutagens. The mutagenicity of most compounds identified as carcinogens for experimental animals has been demonstrated in simple bacterial assays. Because the mutagenic potential of compounds is roughly proportional to their carcinogenic potential, bacterial mutagenesis is the basis for routine tests for carcinogens. The first and most popular of these tests is the Ames test, named for its developer Bruce Ames, a bacterial geneticist. In one version of the test, a chemical is incubated first with a liver extract to allow any metabolic activation to occur; it then is added to several different bacterial cultures designed to detect specific types of mutations. A positive result in the Ames test shows that a compound has the potential to be carcinogenic, but does not indicate how potent it is. The actual danger posed by any chemical is often assessed in animal studies, but even these are not a definitive indication of the danger to humans.
The strongest evidence that carcinogens act as mutagens comes from the observation that cellular DNA altered by exposure of cells to carcinogens can change cultured cells into fast-growing cancer-type cells. This very important result was first obtained by extracting DNA from human cells exposed to a carcinogen or from human colon tumors. The extracted DNA then was applied to normal mouse 3T3 fibroblast cells, which grow as a monolayer on plastic culture dishes and stop dividing when they contact other cells. A small fraction of the treated 3T3 cells took up the DNA and began rapidly proliferating and growing on top of one another to form a pile of cells on the culture dish (see Figure 24-4). Analysis of the DNA from such oncogenically transformed 3T3 cells showed that it had incorporated a segment of human DNA that had undergone a mutation in a normal cellular gene, called a proto-oncogene, involved in the control of cell growth or division. Expression of the mutated human gene caused abnormal proliferation of the 3T3 cells. Mutated forms of proto-oncogenes that cause abnormal cell proliferation are called oncogenes; these can be passed on to other cells and also are carried by certain cancer-causing retroviruses. As discussed in Chapter 24, this type of study has identified a mutation in the ras proto-oncogene as a major contributor to human colon carcinoma. The role of this and other proto-oncogenes in controlling cell growth is described in later chapters.
DNA Damage Can Be Repaired by Several Mechanisms
In addition to the proofreading activity of DNA polymerases that can correct miscopied bases during replication, cells have evolved mechanisms for repairing DNA damaged by chemicals or radiation. Complex organisms with large genomes and relatively long generation times contain many cells that divide very slowly or not at all (e.g., liver and brain cells). Such cells must use the information in their DNA for weeks, months, or even years, greatly increasing their chances for sustaining damage to their DNA. If repair processes were 100 percent effective, chemicals and radiation would pose no threat to cellular DNA. Unfortunately, repair of lesions caused by some environmental agents is relatively inefficient, and such lesions can lead to mutations that ultimately cause cancer. In theory, a carcinogen could act by binding to DNA and causing a change in the sequence that is perpetuated during DNA replication. Current evidence suggests, however, that many permanent DNA sequence changes are induced by the very repair processes cells use to rid themselves of DNA damage.
DNA-repair mechanisms have been studied most extensively in E. coli, using a combination of genetic and biochemical approaches. The remarkably diverse collection of enzymatic repair mechanisms revealed by these studies can be divided into three broad categories:
Mismatch repair, which occurs immediately after DNA synthesis, uses the parental strand as a template to correct an incorrect nucleotide incorporated into the newly synthesized strand.
Excision repair entails removal of a damaged region by specialized nuclease systems and then DNA synthesis to fill the gap.
Repair of double-strand DNA breaks in multicellular organisms occurs primarily by an end-joining process.
We discuss each of these DNA-repair mechanisms in order and then see how defective or error-prone DNA-repair systems can preserve mutations and contribute to tumor formation.
Mismatch Repair of Single-Base Mispairs
Many spontaneous mutations are point mutations, which involve a change in a single base pair in the DNA sequence (see Figure 8-4). These can arise from errors in replication, during genetic recombination, and, particularly, by base deamination whereby a C residue is converted into a U residue (Figure 12-23).
Formation of a spontaneous point mutation by deamination of cytosine (C) to form uracil (U). If the resulting U·G base pair is not restored to the normal C·G base pair by repair mechanisms, it will be fixed in the DNA during replication. (more...)
Bacterial and eukaryotic cells have a mismatch-repair system that recognizes and repairs all single-base mispairs except C·C, as well as small insertions and deletions. The conceptual problem with mismatch repair is determining which is the normal and which is the mutant DNA strand, and repairing the latter so that it is properly base-paired with the normal strand. How this is accomplished has been elucidated in considerable detail for the E. coli methyldirected mismatch-repair system, often referred to as the MutHLS system.
In E. coli DNA, adenine residues in a GATC sequence are methylated at the 6 position. Since DNA polymerases incorporate adenine, not methyl-adenine, into DNA, adenine residues in newly replicated DNA are methylated only on the parental strand. The adenines in GATC sequences on the daughter strands are methylated by a specific enzyme, called Dam methyltransferase, only after a lag of several minutes. During this lag period, the newly replicated DNA contains hemimethylated GATC sequences:
An E. coli protein designated MutH, which binds specifically to hemimethylated sequences, is able to distinguish the methylated parental strand from the unmethylated daughter strand. If an error occurs during DNA replication, resulting in a mismatched base pair near a GATC sequence, another protein, MutS, binds to this abnormally paired segment (Figure 12-24). Binding of MutS triggers binding of MutL, a linking protein that connects MutS with a nearby MutH. This cross-linking activates a latent endonuclease activity of MutH, which then cleaves specifically the unmethylated daughter strand. Following this initial incision, the segment of the daughter strand containing the misincorporated base is excised and replaced with the correct DNA sequence.
Model of mismatch repair by the E. coli MutHLS system. This repair system operates soon after incorporation of a wrong base, before the newly synthesized daughter strand becomes methylated. MutH binds specifically to a hemimethylated GATC sequence, and (more...)
E. coli strains that lack the MutS, MutH, or MutL protein have a higher rate of spontaneous mutations than wild-type cells. Strains that cannot synthesize the Dam methyltransferase also have a high rate of spontaneous mutations. Because Dam− strains cannot methylate adenines within GATC sequences, the MutHLS mismatch-repair system cannot distinguish between the template and newly synthesized strand and therefore cannot efficiently repair mismatched bases.
A similar mechanism repairs lesions resulting from depurination, the loss of a guanine or adenine base from DNA resulting from cleavage of the glycosidic bond between deoxyribose and the base. Depurination occurs spontaneously and is fairly common in mammals. The resulting apurinic sites, if left unrepaired, generate mutations during DNA replication because they cannot specify the appropriate paired base. All cells possess apurinic (AP) endonucleases that cut a DNA strand near an apurinic site. As with mismatch repair, the cut is extended by exonucleases, and the resulting gap then is repaired by DNA polymerase and ligase.
Excision Repair
Cells use excision repair to fix DNA regions containing chemically modified bases, often called chemical adducts, that distort the normal shape of DNA locally. A key to this type of repair is the ability of certain proteins to slide along the surface of a double-stranded DNA molecule looking for bulges or other irregularities in the shape of the double helix. For example, this mechanism repairs thymine-thymine dimers, the most common type of damage caused by UV light (Figure 12-25); these dimers interfere with both replication and transcription of DNA. Excision repair also can correct DNA regions containing bases altered by the attachment of large chemical groups [e.g., carcinogens such as benzo(a)pyrene; see Figure 12-22].
UV irradiation can cause adjacent thymine residues in the same DNA strand to become covalently attached. The resulting thymine-thymine dimer (cyclobutylthymine) may be repaired by an excision-repair mechanism.
Perhaps the best-understood example of excision repair is the UvrABC system from E. coli. Cells carrying mutations in the uvrA, B, or C locus are very sensitive to UV light and chemicals that add large groups to DNA. Figure 12-26 illustrates how the UvrABC system repairs damaged DNA. Initially, a complex comprising two molecules of UvrA and one molecule of UvrB forms and then binds to DNA. Both the formation and binding of this complex to DNA requires ATP. It seems likely that the UvrA-UvrB complex initially binds to an undamaged segment and translocates along the DNA helix until a distortion caused by an adduct is recognized; this translocation along the helix also requires ATP. An ATP-dependent conformational change in the damaged DNA region bound to the UvrA-UvrB complex then produces a bend, or kink, in the DNA backbone. After the UvrA dimer has dissociated, the UvrC protein, which has endonuclease activity, binds to the damaged site. The interaction of UvrC and the bent DNA is thought to open up space within the DNA, allowing the catalytic residues of the enzyme to access their target (Figure 12-27). The precise position of the cleavage sites is determined by the nature of the DNA damage. In the case of thymine dimers, UvrC cleaves two phosphodiester bonds: one is located eight nucleotides 5′ to the lesion, and one is located four or five nucleotides 3′ to the lesion. After UvrC has cleaved the damaged strand at two points, the fragment with the adduct is removed by a helicase and degraded; the gap left in the strand then is repaired by the combined actions of DNA polymerase I and DNA ligase (see Figure 12-26, steps 7 and 8).
Excision repair of DNA by E. coli UvrABC mechanism. Two molecules of UvrA and one of UvrB form a complex that moves randomly along DNA (steps 1 and 2). Once the complex encounters a lesion, conformational changes in DNA, powered by ATP hydrolysis, cause (more...)
Model of complex formed between bacteriophage T4 endonuclease V and a 13-bp DNA fragment containing a thymine-thymine dimer based on x-ray crystallographic analysis. Interaction of the enzyme (top) with the kinked DNA (bottom) causes one of the adenines normally (more...)
End-Joining Repair of Nonhomologous DNA
A cell that has suffered a particular double-strand break usually contains other breaks; such breaks can be repaired by joining the free DNA ends. The joining of broken ends from different chromosomes, however, leads to translocation of pieces of DNA from one chromosome to another (see Figure 8-4b). Such translocations may trigger abnormal cell growth by placing a proto-oncogene next to, and thus under the inappropriate control of, a promoter from another gene. Double-strand breaks are caused by ionizing radiation and by anticancer drugs, such as bleomycin, which is why these drugs are used to kill rapidly growing cells. The devastating effects of double-strand breaks make these the "most unkindest cuts of all," to paraphrase Shakespeare's Julius Caesar.
Double-strand breaks can be correctly repaired only if the free ends of the DNA rejoin exactly. Such repair is complicated by the absence of single-stranded regions that can direct base-pairing during the joining process. One of the two mechanisms that have evolved to repair double-strand breaks is homologous recombination. In this process, as described later, the double-strand break on one chromosome is repaired using the information on the homologous, intact chromosome.
In multicellular organisms, however, the predominant mechanism for repairing double-strand breaks involves rejoining the ends of the two DNA molecules. Although this process, outlined in Figure 12-28, yields a continuous double-stranded molecule, it results in loss of several base pairs at the joining point. Formation of such a possibly mutagenic deletion is one example of how repair of DNA damage can introduce mutations. A similar process can link together any two DNA molecules, even those cut from different chromosomes.
Repair of double-strand breaks by end-joining of nonhomologous DNAs (dark and light blue), that is, DNAs with dissimilar sequences at their ends. These DNAs could be cut fragments from a single gene, or DNAs cut from different chromosomes. A complex of (more...)
Eukaryotes Have DNA-Repair Systems Analogous to Those of E. coli
Evidence is accumulating that the basic mechanisms of DNA repair have been conserved during evolution. For example, recent biochemical studies have shown that human cells carry out mismatch repair by a process similar to that in E. coli (see Figure 12-24). The repair process can be initiated by the human MutSα protein, a homolog of bacterial MutS, which binds both to mismatched base pairs and to small insertions or deletions, or by MutSβ, which binds mainly to insertions and deletions. The human MutL protein is recruited to the DNA by MutSα or MutSβ, but the identity of the human nuclease (equivalent to MutH in E. coli) that actually cuts the DNA is unknown. Following cleavage, which can occur either 3′ or 5′ to the mismatch, an exonuclease removes 100 – 200 nucleotides from the cut strand, spanning the mismatch. DNA polymerase δ is principally responsible for filling in the gap, following which the strands are sealed by the action of a DNA ligase.
Genetic studies in eukaryotes ranging from yeast to humans suggest that quite similar excision-repair mechanisms are employed by different organisms. The basic strategy is to search for mutants that exhibit increased sensitivity to UV light or other agents that produce shape-distorting lesions in DNA. Such mutants presumably are deficient in the wild-type excision-repair mechanisms that normally repair damage caused by such agents. In the yeast S. cerevisiae, for instance, numerous UV-sensitive mutants and 10 radiation- sensitive (RAD) genes have been identified. Techniques of somatic-cell genetics have been used to generate mutant Chinese hamster ovary (CHO) cell lines that are abnormally sensitive to UV light or to DNA damage caused by mitomycin C, which forms bulky adducts with DNA. These mutations fall into eight complementation groups, suggesting that at least eight different genes are involved in excision repair in hamsters. DNA transfection experiments have revealed that certain human genes can rescue some UV-sensitive CHO cell mutants. Two of the human genes identified in this way have been shown to be related to the yeast RAD3 and RAD10 genes. The human protein with partial homology to the RAD10 protein also contains a region that is similar to part of E. coli UvrC.
Remarkably, five polypeptides required for excision repair in eukaryotic cells, including two with homology to helicases, are also subunits of TFIIH, a general transcription factor required by RNA polymerase II (see Figure 10-50). It appears that Nature has used a similar protein assembly in two different cellular processes that require helicase activity. The use of shared subunits in transcription and DNA repair may help explain transcription-coupled repair. This phenomenon is the observed removal of DNA damage in higher eukaryotes at a much faster rate from regions of the genome being actively transcribed than from nontranscribed regions of the genome. (Recall that in higher eukaryotes, only a small fraction of the genome is transcribed in any one cell.)
Inducible DNA-Repair Systems Are Error-Prone
When a cell suffers so much DNA damage over a short time that its repair systems are saturated, it runs the danger of extensively replicating unrepaired lesions, thereby perpetuating mutations. In such situations, both bacterial and animal cells use inducible repair systems in an attempt to catch up. Such systems are not expressed in undamaged cells, but some aspect of the accumulated damage causes their derepression (induction) and expression.
One such inducible system is the SOS repair system of bacteria. Because this system generates many errors in the DNA as it repairs lesions, it is referred to as error-prone. The SOS system, which repairs UV-induced damage, differs from the constitutive UvrABC system already discussed in that its activity is dependent on RecA protein; as discussed later, RecA also participates in homologous recombination. The errors induced by the SOS system are at the site of lesions, suggesting that the mechanism of repair is insertion of random nucleotides in place of the damaged ones in the DNA. This inducible system is used only as a last resort when error-free mechanisms of repair cannot cope with damage. Bacteria lacking an SOS system will retain mutations caused by UV damage or chemicals, but still will have greatly reduced rates of mutation induced by these agents. This supports the idea that most of the mutations produced by treating bacteria with radiation or chemicals are caused by the error-prone SOS repair system, not by the original lesions themselves.
Animal cells also have inducible repair systems, although it is not known whether these are error-prone. As noted earlier, however, the main mechanism for repairing double-strand breaks in eukaryotes clearly is error-prone (see Figure 12-28). Thus, double-strand repair and, perhaps, error-prone inducible repair likely play a role in mutagenesis and therefore in carcinogenesis in animals. In any case, many investigators believe that in animal cells, as in bacteria, most mutations are an indirect, not direct, consequence of DNA damage.
Because radiation- or carcinogen-induced DNA damage must be repaired before the DNA is replicated, cells have sensing mechanisms that react to DNA damage and stop DNA replication. These mechanisms, which are discussed in detail in the next chapter, involve checkpoint control proteins such as the p53 protein, which acts to stop the cell cycle if DNA is damaged, and thus to suppress production of tumors. Cells that do not express functional p53 protein exhibit high rates of mutation in response to DNA damage, accelerating the formation of tumors.
Changes in the DNA sequence result from copying errors and the effects of various physical and chemical agents, or carcinogens. All carcinogens are mutagens; that is, they alter one or more nucleotides in DNA.
The varied structures of chemical carcinogens have one unifying characteristic: electrophilic reactivity (either they are electrophiles or they are metabolized in the body to become electrophiles). Metabolic activation occurs via the cytochrome P-450 system, a pathway generally used by cells to rid themselves of noxious chemicals.
Many copying errors that occur during DNA replication are corrected by the proofreading function of DNA polymerases that can recognize incorrect (mispaired) bases at the 3′ end of the growing strand and then remove them by an inherent 3′ → 5′ exonuclease activity (see Figure 12-21).
In mismatch repair, a short section of a newly synthesized DNA strand containing an incorrect base is identified, removed, and replaced by DNA synthesis directed by the correct template (see Figure 12-24).
In excision repair, bulky lesions in DNA resulting from exposure to UV light and various chemicals are removed (excised) by specialized nuclease systems; DNA synthesis by a polymerase fills the gap and ligase joins the free ends (see Figure 12-26).
Double-strand breaks can be repaired by homologous recombination and by an end-joining of nonhomologous DNA duplexes. In the latter process, several bases at the site of the break are removed (see Figure 12-28).
Both bacterial and eukaryotic cells have inducible DNA-repair systems, which are expressed when DNA damage is so extensive that replication may occur before constitutive mechanisms can repair all the damage. The inducible SOS repair system in bacteria is error-prone and thus generates and perpetuates mutations.
DNA-repair mechanisms that are ineffective or error-prone may perpetuate mutations. This is a major way by which DNA damage, caused by radiation or chemical carcinogens, induces tumor formation. Thus, cellular DNA-repair processes have been implicated both in protecting against and contributing to the development of cancer.
Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK21554
Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 12.4, DNA Damage and Repair and Their Role in Carcinogenesis.
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