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The Role of Carcinogens and DNA Repair in Cancer

In this final section, we examine how alterations in the genome arise that may lead to cancer and how cells attempt to correct them. DNA damage is unavoidable and arises by spontaneous cleavage of chemical bonds in DNA, by reaction with genotoxic chemicals in the environment or with certain chemical by-products of normal cellular metabolism, and from environmental agents such as ultraviolet and ionizing radiation. Changes in the DNA sequence can also result from copying errors introduced by DNA polymerases during replication and by mistakes made when DNA polymerase attempts to read from a damaged template. If DNA sequence changes, whatever their cause or nature, are left uncorrected, both proliferating and quiescent somatic cells might accumulate so many mutations that they could no longer function properly. In addition, the DNA in germ cells might incur too many mutations for viable offspring to be formed. Thus the prevention of DNA sequence errors in all types of cells is important for survival, and several cellular mechanisms for repairing damaged DNA and correcting sequence errors have evolved.

As our previous discussion has shown, alterations in DNA that lead to decreased production of functional tumor-suppressor proteins or increased, unregulated production or activation of oncoproteins are the underlying cause of most cancers. These oncogenic mutations in key growth and cell-cycle regulatory genes include insertions, deletions, and point mutations, as well as chromosomal amplifications and translocations. Most cancer cells lack one or more DNA-repair systems, which may explain the large number of mutations that they accumulate. Moreover, some repair mechanisms themselves introduce errors in the nucleotide sequence; such error-prone repair also contributes to oncogenesis. The inability of tumor cells to maintain genomic integrity leads to formation of a heterogeneous population of malignant cells. For this reason, chemotherapy directed toward a single gene or even a group of genes is likely to be ineffective in wiping out all malignant cells. This problem adds to the interest in therapies that interfere with the blood supply to tumors or in other ways act upon multiple types of tumor cells.

▲ FIGURE 23-24 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 strand, and the polymerase catalytic activity (Pol) lies in the junction between the fingers and palm. As long as the correct nucleotides are added to the 3' end of the growing strand, it remains in the polymerase site. Incorporation of an incorrect base at the 3' end causes melting of the newly formed end of the duplex. As a result, the polymerase pauses, and the 3' end of the growing strand is transferred to the 3' n 5' exonuclease site (Exo) about 3 nm away, where the mispaired base and probably other bases are removed. Subsequently, the 3' end flips back into the polymerase site and elongation resumes. [Adapted from C. M. Joyce and T. T Steitz, 1995, J. Bacteriol. 177:6321, and S. Bell and T Baker, 1998, Cell 92:295.]

DNA Polymerases Introduce Copying Errors and Also Correct Them

The first line of defense in preventing mutations is DNA polymerase itself. Occasionally, when replicative DNA poly-merases progress along the template DNA, an incorrect nu-cleotide is added to the growing 3' end of the daughter strand (see Figure 4-34). E. coli DNA polymerases, for instance, introduce about 1 incorrect nucleotide per 104 polymerized nucleotides. Yet the measured mutation rate in bacterial cells is much lower: about 1 mistake in 109 nucleotides incorporated into a growing strand. This remark-

able accuracy is largely due to proofreading by E. coli DNA polymerases.

Proofreading depends on the 3'n5' exonuclease activity of some DNA polymerases. 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 incorrect mispaired base is removed (Figure 23-24). Then the 3' end is transferred back to the polymerase site, where this region is copied correctly. All three E. coli DNA polymerases have proofreading activity, as do the two DNA polymerases, 8 and e, used for DNA replication in animal cells. It seems likely that proofreading is indispensable for all cells to avoid excessive mutations.

► FIGURE 23-25 Formation of a spontaneous point mutation by deamination of 5-methyl cytosine (C) to form thymine (T). If the resulting T • G base pair is not restored to the normal C • G base pair by base excision-repair mechanisms (1), it will lead to a permanent change in sequence following DNA replication (i.e., a mutation) ( 2|). After one round of replication, one daughter DNA molecule will have the mutant T-A base pair and the other will have the wild-type C-G base pair.

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