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Regulation of Single-Strand Annealing and its Role in Genome Maintenance - PubMed

Review

Regulation of Single-Strand Annealing and its Role in Genome Maintenance

Ragini Bhargava et al. Trends Genet. 2016 Sep.

Abstract

Single-strand annealing (SSA) is a DNA double-strand break (DSB) repair pathway that uses homologous repeats to bridge DSB ends. SSA involving repeats that flank a single DSB causes a deletion rearrangement between the repeats, and hence is relatively mutagenic. Nevertheless, this pathway is conserved, in that SSA events have been found in several organisms. In this review, we describe the mechanism of SSA and its regulation, including the cellular conditions that may favor SSA versus other DSB repair events. We will also evaluate the potential contribution of SSA to cancer-associated genome rearrangements, and to DSB-induced gene targeting.

Keywords: RAD51; RAD52; alternative end joining; end resection; homology directed repair; single-strand annealing.

Copyright © 2016 Elsevier Ltd. All rights reserved.

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Figures

Figure 1
Figure 1

Key Figure. Comparisons between Single Strand Annealing (SSA) and distinct double-strand break (DSB) repair events: Homology Directed Repair (HDR), Alternative End Joining (ALT-EJ), and Canonical Non-Homologous End Joining (C-NHEJ). End resection is depicted as a common intermediate of SSA, HDR, and ALT-EJ. In the subsequent steps of SSA, homologous repeats (depicted as rust colored boxes) anneal to form the synapsis intermediate that is then processed for ligation. The RAD51 recombinase is shown to inhibit SSA, and conversely mediate the strand invasion step of HDR.

Figure 2
Figure 2

Shown are key distinctions between ALT-EJ and SSA, with diagrams of the annealed/synapsed intermediate for each pathway. Distinct features include the extent of end resection involved and hence the length of 3′ ssDNA that is cleaved during processing of this intermediate, the length of the homologous repeat involved in the annealing, and the relative role of PARP and Polθ versus RAD52. The precise boundaries of these features that define ALT-EJ versus SSA remain unclear. Indeed, we represent the possibility that these features exist along a spectrum with a middle region that could potentially be repaired by either pathway. For example, it is conceivable that intermediate lengths of annealed homology are repaired by either ALT-EJ or SSA (i.e. mediated by PARP and Polθ, or RAD52). Similarly, a moderate extent of resection could be sufficient to reveal such intermediate lengths of flanking homology. However, it is also possible one or more of these features have defined boundaries that distinguish repair by ALT-EJ versus SSA.

Figure 3
Figure 3

Shown is a model for the influence of cell cycle phase and the presence of the sister chromatid on DSB repair pathways. G1 phase is shown as being suppressed for end resection, such that a DSB in this context would likely be repaired by C-NHEJ. S/G2 phases are shown as permissive for end resection. The middle chromosome diagram shows a DSB occurring in S-phase but before this particular chromosome (or at least the region at the DSB) has been replicated. In this context, the sister chromatid is unavailable for HDR, such that if this DSB is resected, it will likely be repaired by SSA or ALT-EJ. In contrast, the chromosome on the right has been replicated prior to DSB formation, such that HDR with the sister chromatid template is feasible. Thus, HDR is depicted as favored in this context over SSA or ALT-EJ (i.e. the solid line versus the dashed lines). Also shown is the notion that DSBs are not necessarily end resected in S/G2, such that C-NHEJ is active throughout the cell cycle.

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