Figure 6.2

Mechanism of double strand break repair by homologous recombination through hybridization of the broken DNA strands sequences on the undamaged homolog. A DNA terminus is paired with the intact DNA by the action of pairing proteins including Rad51 and many other associated proteins that modulate its functions and carry out the numerous steps of pairing, elongation of DNA termini, and migration of hybridizing junction regions. Conformation changes produce a Holliday junction (a + form, 4-stranded junction) which is a strong binding site for p53, and which is resolved into separate DNA double helices containing regions of exchange, by junction-specific nucleases. The extent of sequence overlap can be very long, up to kilobases in length, and requires exact matching of DNA along most of the length of the hybrid molecules. Rad51-dependent DNA pairing is suppressed by p53-rad51 interaction, which is also a route for initiating intracellular p53-dependent signal transduction pathways. Broken double stranded DNA indicated by a,b; recipient intact strands by c,d; strands created by strand extension c', d'. De novo synthesis indicated by ——. Repair of a double strand break will require two of these homologous exchange events, one for each terminus. Some resolved DNA products may be visualized at the chromosomal level in mitotic cells as a sister chromatid exchange.

Little 1992). The relative importance of those pathways can vary with cell-cycle stage, tissue type, developmental stage and species. Direct measurement of DNA breakage and repair indicates that double-strand breaks can be rejoined rapidly—within a few hours. There is, however, a residuum of unrepaired damage that is greater for densely ionizing radiation, such as alpha particles, than for x rays (Ager and others 1991; Iliakis 1991; Iliakis and others 1990; Ward 1990). Although it is unknown if high levels of alpha-particle damage saturate DNA-repair systems, such potential saturation would not be relevant at low-dose ambient



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement