Mechanisms for fragile site stimulated mitotic crossovers and BIR events.

<p>In cells with low levels of polymerase alpha, slowed DNA replication likely results in larger regions of single-stranded DNA on the lagging strand, which allows intra-strand pairing at FS2 to form a hairpin. Here, the MS71-derived homolog of chromosome III is depicted in gray, with the two inverted Ty1 elements of FS2 as black arrows. Stalling could be followed by either cleavage at the secondary structure, resulting in fork collapse, or replication may proceed and leave a single-strand gap at the secondary structure. Fork collapse to a one-ended double-strand break is expected to primarily stimulate repair by BIR. Here, the homologous YJM789-derived chromosome III is shown in red as a repair template, resulting in LOH. If a replication from a nearby origin converges with the collapsed fork, a double-strand break will form. This lesion can be repaired by invasion of the red, YJM789-derived homolog, and capture of the second end, as shown. Crossover resolution of the double Holliday junction can result in LOH after mitotic chromosome segregation. If replication stalling results in formation of a single-strand gap rather than a break, template switching may be used to fill the gap. Template switch to the red, YJM789-derived homolog forming a double Holliday junction is shown. Crossover resolution followed by mitotic chromosome segregation can result in LOH.