Keep moving and stay in a good shape to find your homologous recombination partner

Abstract

Genomic DNA is constantly exposed to damage. Among the lesion in DNA, double-strand breaks (DSB), because they disrupt the two strands of the DNA double helix, are the more dangerous. DSB are repaired through two evolutionary conserved mechanisms: Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Whereas NHEJ simply reseals the double helix with no or minimal processing, HR necessitates the formation of a 3'ssDNA through the processing of DSB ends by the resection machinery and relies on the recognition and pairing of this 3'ssDNA tails with an intact homologous sequence. Despite years of active research on HR, the manner by which the two homologous sequences find each other in the crowded nucleus, and how this modulates HR efficiency, only recently emerges. Here, we review recent advances in our understanding of the factors limiting the search of a homologous sequence during HR.

Keywords: DSB; Heterochromatin; Homologous recombination; Homology search; Nuclear organization; Resection.

Fig. 1

A When a DSB occurs on a locus which is in close spatial proximity to the recombination donor, the two sites can encounter after resection has unmasked homologous sequences but prior elimination of the homologous sequence. The homology search process is then productive and recombination repair successful. B If the DSB and the recombination donor are too distant, resection will shrink DSB flanking sequences eliminating homologous sequences prior encounter with the donor locus. DSB and global genome-induced mobility can eventually favour timely encounter. C The limitation of resection progression by a compact chromatin structure can provide the time for the moving DSB to find the homologous donor and allow a productive homology search