Cell Cycle Features

A double-strand DNA break (DSB) represents a potentially lethal form of DNA damage. DSBs are generated upon exposure to ionizing radiation and chemical mutagens. In addition, they arise from replica-tion of imperfect chromosomal DNA, and during meiotic and V(D) J recombination. It is estimated that a normal human cell accurately repairs approximately 50 breaks every cell cycle.1 How is this achieved? The easiest option is to simply reconnect the broken ends. Non-homologous end joining (NHEJ) achieves this goal and, it has the advantage that it can occur throughout the cell cycle2 without the need for a template (Fig. 1A). Though effective, NHEJ has two potential pitfalls: first, without a template, incorrectly ligated DSB ends produce chromosomal rearrangements, and second, genetic information is lost if the DNA ends are altered before re-ligation. The alternative is homologous recombination (HR). HR is far more accurate, but is constrained by the requirement for an intact homologous template. It is regulated to occur mainly during S and G2 stages of cell cycle when the homologous sister chromatid is present2,3 (Fig. 1A). The steps involved in the repair of DSBs by HR were elegantly described by Szostak et al.4 (Fig. 1B). The repair of DSBs starts with resection of the 5 ’ termini at both ends of the break. This processing is crucial because it generates single-strand DNA (ssDNA) that serves as the substrate for assembly of a RecA/Rad51 nucleoprotein filament that searches for DNA homology. Once found, the processed end invades the homologous DNA to form a recombination intermediate called a joint molecule or displacement loop (D-loop). The invaded strand then primes DNA synthesis using the intact homologous chro-mosome as a template to restore genetic material lost by resection. Subsequently, the resected second-end pairs, and more DNA synthesis restores the lost genetic information. In the DSB repair (DSBR) model, it was recognized that the second processed end of the DNA break could engage with the joint molecule by two alternative mechanisms