FIGURE 1-12 HR- and microhomology-mediated DSB repair. These two pathways for repair of DSBs are driven by stretches of homologous DNA. HR requires an identical sequence spanning the part of the DNA molecule containing the break and extensive remodeling of the broken DNA termini. Mre11/Rad50/Nbs1 resects individual strands by its 5′- to 3′-exonuclease activity and binds homologous double-stranded DNA by the Rad50 moiety. Exposure of single-stranded regions with only small regions of homology flanking the original break can allow microhomology-mediated strand-break rejoining coupled by cleavage of overhanging strands by FEN1 and resynthesis of any resulting gaps. The repair will, at the least, result in loss of one of the regions of microhomology. Exposure of single-stranded regions homologous to adjacent double-stranded DNA can lead to strand invasion and HR. Single-stranded regions are coated with single-strand binding protein (RPA); homology search and strand invasion are mediated by Rad52, 54, Brca 1 and 2, and Rad51. The complex structure produced forms a Holliday junction that is cleaved by junction-specific nucleases (resolvases), and associated polymerase and ligases complete an error-free exchange of DNA strands. SOURCE: Modified reproduction and reproduced with permission of J. Hoeijmakers (2001).