Collaboration and competition between DNA double-strand break repair pathways

Abstract

DNA double-strand breaks resulting from normal cellular processes including replication and exogenous sources such as ionizing radiation pose a serious risk to genome stability, and cells have evolved different mechanisms for their efficient repair. The two major pathways involved in the repair of double-strand breaks in eukaryotic cells are non-homologous end joining and homologous recombination. Numerous factors affect the decision to repair a double-strand break via these pathways, and accumulating evidence suggests these major repair pathways both cooperate and compete with each other at double-strand break sites to facilitate efficient repair and promote genomic integrity.

Fig. 1

Competition between double-strand break repair pathways. DNA double-strand breaks (DSBs) are repaired by two distinct pathways, homologous recombination (HR) and non-homologous end joining (NHEJ). HR is initiated by 5′ to 3′ end resection, forming a 3′ single-stranded tail onto which Rad51 assembles. The Rad51 nucleoprotein filament allows single-strand DNA invasion into a homologous duplex, typically the sister chromatid, to initiate repair synthesis. The newly synthesized strand is then displaced to anneal to the other DNA end (not shown) to complete the HR reaction. When a DSB and subsequent end resection occurs at sequence repeats (green lines), an alternative pathway, single-strand annealing (SSA), can take place. The complementary single strands at the repeats can anneal, giving rise to a copy number variant, in this case a product with a single copy of the repeat and a deletion of the intervening sequence. NHEJ involves the joining of DNA ends with no or little homology (microhomology). In this pathway, the Ku heterodimer binds to DNA ends, protecting them from end resection. A number of processing factors are subsequently recruited (not shown), which allows a variety of end structures to be joined. Mutational analysis has demonstrated that factors involved in HR and NHEJ likely directly “compete” at steps indicated by the numbers: (1) loss of canonical NHEJ factors (Ku, DNA ligase IV/XRCC4) leads to increased end resection and hence HR and SSA. (2) End resection mutants (e.g., Sae2) have increased NHEJ. (3) Disruption of Rad51 filament formation allows DNA ends to be channeled into SSA.