Leaping forks at inverted repeats

Abstract

Genome rearrangements are often associated with genome instability observed in cancer and other pathological disorders. Different types of repeat elements are common in genomes and are prone to instability. S-phase checkpoints, recombination, and telomere maintenance pathways have been implicated in suppressing chromosome rearrangements, but little is known about the molecular mechanisms and the chromosome intermediates generating such genome-wide instability. In the December 15, 2009, issue of Genes & Development, two studies by Paek and colleagues (2861-2875) and Mizuno and colleagues (pp. 2876-2886), demonstrate that nearby inverted repeats in budding and fission yeasts recombine spontaneously and frequently to form dicentric and acentric chromosomes. The recombination mechanism underlying this phenomenon does not appear to require double-strand break formation, and is likely caused by a replication mechanism involving template switching.

Figure 1.

Template switch events at nearby inverted repeats. Inverted repeats are shown in red, the DNA segment interrupting the repeats are shown in black, and the newly synthesized DNA are shown in blue. In A, the DNA segment containing the inverted repeats (palindrome) adopts a cruciform structure. One replication fork arrests within the repeat and can invade the one of the opposite repeat (Mizuno et al. 2009). In B, the nearby inverted repeats are separated by longer DNA segments, but chromatin looping can bring these elements into physical proximity. Slowing down or fork arrest during replication of the repeat sequence will lead to accumulation of positive supercoil ahead of the replication fork, and this can induce fork regression (Olavarrieta et al. 2002). Following reversal of the four-way junction (Atkinson and McGlynn 2009), one of the newly synthesized strands containing some segment of one of the repeat sequences can reanneal (reinvade) to the wrong repeat sequence, leading to the fusion (joining) of the repeat sequences (Paek et al. 2009).