Info

Base pairing with other damaged strand

Site of pairing

DNA polymerase, â–  ligase

Gap filling and ligation

5' i i i i i i i i i i i i m i i i i i i i i i i i i i i i 3'

4 FIGURE 23-31 Repair of double-strand breaks by homologous recombination. During S phase cells copy each chromosome to create two identical sister chromatids that later segregate into daughter cells. The black and red DNAs represent the homologous sequences on these sister chromatids. Step 1: A double-strand DNA break forms in the chromatids. Step 2: The double-strand break activates the ATM kinase (see Figure 23-23); this leads to activation of a set of exonucleases that remove nucleotides at the break first from the 3' and then from the 5' ends of both broken strands, ultimately creating single-stranded 3' ends. In a process that is dependent on the BRCA1 and BRCA2 proteins, as well as others, the Rad51 protein (green ovals) polymerizes on single-stranded DNA with a free 3' end to form a nucleoprotein filament. Step 3: Aided by yet other proteins, one Rad51 nucleoprotein filament searches for the homologous duplex DNA sequence on the sister chromatid, then invades the duplex to form a joint molecule in which the single-stranded 3' end is base-paired to the complementary strand on the homologous DNA strand. Step 4: The replicative DNA polymerases elongate this 3' end of the damaged DNA (green strand), templated by the complementary sequences in the undamaged homologous DNA segment. Step 5: Next this repaired 3' end of the damaged DNA pairs with the single-stranded 3' end of the other damaged strand. Step 6: Any remaining gaps are filled in by DNA polymerase and ligase (light green), regenerating a wild-type double helix in which an entire segment (dark and light green) has been regenerated from the homologous segment of the sister chromatid. [Adapted from D. van Gant et al., 2001, Nature Rev. Genet. 2:196.]

system facilitated study of the process. Virtually all the yeast Rad proteins have homologs in the human genome, and the human and yeast proteins function in an essentially identical fashion (Figure 23-31). At one time homologous recombination was thought to be a minor repair process in human cells. This changed when it was realized that several human cancers are potentiated by inherited mutations in genes essential for homologous recombination repair (see Table 23-1). For example, the vast majority of women with inherited susceptibility to breast cancer have a mutation in one allele of either the BCRA-1 or the BCRA-2 genes that encode proteins participating in this repair process. Loss or inactivation of the second allele inhibits the homologous recombination repair pathway and thus tends to induce cancer in mammary or ovarian epithelial cells.

Repair of a double-strand break by homologous recombination involves reactions between three DNA molecules— the two DNA ends and the intact DNA strands from the sister chromatid (see Figure 23-31). In this process single-stranded DNAs with 3' ends are formed from the ends of the broken DNAs and then coated with the Rad51 protein. One Rad51 nucleoprotein filament searches for the homologous duplex DNA sequence in the sister chromatid. This 3' end is then elongated (green in Figure 23-31) by DNA poly-merase, templated by the complementary strand on the homologous DNA. When sufficiently long, this single strand

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