Repair Pathway Choices and Consequences at the Double-Strand Break

Abstract

DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate end-joining events, which commonly underlie oncogenic transformation due to chromosomal translocations. Typically, cells employ two main mechanisms to repair DSBs: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alternative error-prone DSB repair pathways, namely alternative end joining (alt-EJ) and single-strand annealing (SSA), have been recently shown to operate in many different conditions and to contribute to genome rearrangements and oncogenic transformation. Here, we review the mechanisms regulating DSB repair pathway choice, together with the potential interconnections between HR and the annealing-dependent error-prone DSB repair pathways.

Way out/way in: How the relationship between WRN and CDK1 may change the fate of collapsed replication forks

“…5 The molecular mechanism underlying HR is pretty well defined, and it is initiated by processing of DNA ends by nucleases to produce singlestrand DNA (ssDNA) tails that will be recognized by the major recombinase RAD51 to perform strand invasion and exchange. 5 As a limiting step, resection of the DSB is tightly regulated and used as a switch to select for different DNA repair pathways. Indeed, the competition for DNA ends between HR and NHEJ factors implicates efficient formation of ssDNA as critical to promote loading of one class of factors or the other one.…”

“…Indeed, the competition for DNA ends between HR and NHEJ factors implicates efficient formation of ssDNA as critical to promote loading of one class of factors or the other one. 5 Resection is initiated by the MRE11 nuclease, part of a complex comprising also RAD50 and NBS1. Subsequently, the EXO1 or DNA2 exonucleases, in combination with the helicase activity of two RecQ-class proteins, the Bloom's syndrome (BLM), or the Werner's syndrome protein (WRN), take over in the process.…”

“…5 In higher eukaryotes, the repair of DSBs is performed by homologous recombination (HR), single-strand annealing, and non-homologous end joining (NHEJ). 5 The molecular mechanism underlying HR is pretty well defined, and it is initiated by processing of DNA ends by nucleases to produce singlestrand DNA (ssDNA) tails that will be recognized by the major recombinase RAD51 to perform strand invasion and exchange. 5 As a limiting step, resection of the DSB is tightly regulated and used as a switch to select for different DNA repair pathways.…”

“…The precise view of all the factors implicated in the repair of a replication-dependent DSB is far to be complete; however, the pathways involved are basically those in charge of the repair of classical two-sided DSBs. 5 In higher eukaryotes, the repair of DSBs is performed by homologous recombination (HR), single-strand annealing, and non-homologous end joining (NHEJ). 5 The molecular mechanism underlying HR is pretty well defined, and it is initiated by processing of DNA ends by nucleases to produce singlestrand DNA (ssDNA) tails that will be recognized by the major recombinase RAD51 to perform strand invasion and exchange.…”

“…Regulation of this process is performed by a coordinate phosphorylation of critical resection factors, including EXO1, DNA2 or CtIP, by the cell cycle kinase CDK1 and the DNA damage response factor ATM. 5 In our paper, we wanted to decipher the regulation of one of the crucial end-resection helicases, the WRN protein, in response to replication-dependent DSBs. 6 Indeed, although a key role of WRN during end-resection has not been firmly demonstrated, WRN-deficient cells are extremely sensitive to inhibitors of Topoisomerase I and II, 7,8 showing enhanced replication stalling events and chromosome instability that might be related to defects in repairing replication-dependent DSBs.…”