Fouquin Alexis, Guirouilh-Barbat Josée, Lopez Bernard, Hall Janet, Amor-Guéret Mounira, Pennaneach Vincent
Institut Curie, PSL Research University, UMR 3348, 91405 Orsay, France.
CNRS, UMR3348, Centre Universitaire, Bât. 110, 91405 Orsay, France.
Nucleic Acids Res. 2017 Dec 1;45(21):12325-12339. doi: 10.1093/nar/gkx881.
Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using various lengths of homology. Mechanisms that control the resection initiation are thus central to the regulation to the choice of DSB repair pathway. Therefore, understanding the mechanisms which regulate the initiation of DNA end-resection is of prime importance. Our findings reveal that poly(ADP-ribose) polymerase 2 (PARP2) is involved in DSBR pathway choice independently of its PAR synthesis activity. We show that PARP2 favors repair by homologous recombination (HR), single strand annealing (SSA) and alternative-end joining (A-EJ) rather than the C-EJ pathway and increases the deletion sizes at A-EJ junctions. We demonstrate that PARP2 specifically limits the accumulation of the resection barrier factor 53BP1 at DNA damage sites, allowing efficient CtIP-dependent DNA end-resection. Collectively, we have identified a new PARP2 function, independent of its PAR synthesis activity, which directs DSBs toward resection-dependent repair pathways.
双链断裂（DSBs）是对细胞毒性最大的损伤之一。通过经典非同源末端连接（C-EJ）途径进行的DSB修复，即使有也只涉及对断裂DNA末端的少量加工，而DNA切除的起始则将断裂末端导向使用不同长度同源性的DNA修复途径。因此，控制切除起始的机制对于DSB修复途径选择的调控至关重要。所以，了解调控DNA末端切除起始的机制至关重要。我们的研究结果表明，聚（ADP-核糖）聚合酶2（PARP2）独立于其PAR合成活性参与DSBR途径的选择。我们发现PARP2倾向于通过同源重组（HR）、单链退火（SSA）和替代末端连接（A-EJ）进行修复，而不是C-EJ途径，并增加A-EJ连接处的缺失大小。我们证明PARP2特异性地限制了切除屏障因子53BP1在DNA损伤位点处的积累，从而实现有效的CtIP依赖性DNA末端切除。总体而言，我们确定了PARP2的一种新功能，该功能独立于其PAR合成活性，可将DSBs导向依赖切除的修复途径。
