Building up and breaking down: mechanisms controlling recombination during replication.
The complete and faithful duplication of the genome is an essential prerequisite for proliferating cells to maintain genome integrity. This objective is greatly challenged by DNA damage encountered during replication, which causes fork stalling and in certain cases, fork breakage. DNA damage tolerance (DDT) pathways mitigate the effects on fork stability induced by replication fork stalling by mediating damage-bypass and replication fork restart. These DDT mechanisms, largely relying on homologous recombination (HR) and specialized polymerases, can however contribute to genome rearrangements and mutagenesis. There is a profound connection between replication and recombination: recombination proteins protect replication forks from nuclease-mediated degradation of the nascent DNA strands and facilitate replication completion in cells challenged by DNA damage. Moreover, in case of fork collapse and formation of double strand breaks (DSBs), the recombination factors present or recruited to the fork facilitate HR-mediated DSB repair, which is primarily error-free. Disruption of HR is inexorably linked to genome instability, but the premature activation of HR during replication often leads to genome rearrangements. Faithful replication necessitates the downregulation of HR and disruption of active RAD51 filaments at replication forks, but upon persistent fork stalling, building up of HR is critical for the reorganization of the replication fork and for filling-in of the gaps associated with discontinuous replication induced by DNA lesions. Here we summarize and reflect on our understanding of the mechanisms that either suppress recombination or locally enhance it during replication, and the principles that underlie this regulation.
a IFOM, the FIRC Institute of Molecular Oncology , Milan , Italy.
Dana
0000-0002-0544-4888
D
Branzei
a IFOM, the FIRC Institute of Molecular Oncology , Milan , Italy.
Barnabas
0000-0001-6888-1383
B
Szakal
D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D006801:Humans; D011995:Recombination, Genetic
Chromosome replication; DNA damage; Esc2; MMS22-TONSL; SUMO; SUMO-targeted ubiquitin ligase; Srs2 and RecQ helicases; postreplicative chromatin