FIG. 7.

Extensive LOH resulting from allelic recombination can be suppressed at a number of steps. The overall frequency of allelic recombination can be suppressed by decreasing either the frequency of DSB formation (i) or the efficiency of strand invasion of a broken end into the homologous chromosome (ii). Strand invasion results in D-loop formation and priming of DNA synthesis, as shown. Normally this intermediate would be converted to a product with short regions of LOH by joining of the nascent strand, after minimal DNA synthesis, to the other side of the DSB (data not shown). However, this D-loop intermediate can instead be processed into either of two pathways that result in extensive LOH. (A) LOH by crossing over. In this pathway, the D-loop intermediate is converted to a double Holliday junction, which can be resolved to a crossover product (as shown) or a noncrossover product (data not shown). Thus, crossing over may normally be suppressed by inhibiting Holliday junction formation (iii) or resolution to a crossover product (iv). LOH by crossing over requires that the recombinant chromatids segregate into separate daughter cells. It is formally possibly that this step is suppressed as well (v), such that recombinant chromatids would instead cosegregate into the same daughter cell. However, a recent study suggests that recombinant chromatids can segregate away from each other at detectable frequencies (28). (B) LOH by break-induced replication. In this pathway, the D-loop intermediate persists and migrates to the end of the chromosome arm as a result of extensive leading-strand synthesis. Lagging-strand synthesis results in replication of the noninvading strand. The other end of the chromosome arm is lost during this process. Thus, LOH by break-induced replication can be suppressed by inhibiting either extensive replication (vi) or loss of a chromosome arm (vii).