Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.
Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.
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DOI：
10.1016/j.molcel.2021.06.011
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发表时间：
2021-08-05
期刊：
影响因子：
16
通讯作者：
Cantor, Sharon B.
中科院分区：
文献类型：
--
作者：
Cong, Ke;Peng, Min;Kousholt, Arne Nedergaard;Lee, Wei Ting C.;Lee, Silviana;Nayak, Sumeet;Krais, John;VanderVere-Carozza, Pamela S.;Pawelczak, Katherine S.;Calvo, Jennifer;Panzarino, Nicholas J.;Turchi, John J.;Johnson, Neil;Jonkers, Jos;Rothenberg, Eli;Cantor, Sharon B.
BRCA1或BRCA2(BRCA)的突变是由聚(ADP-核糖)聚合酶抑制剂(PARPI)合成致死的。致死性被认为来自DNA双链断裂(DSB)，使得BRCA在同源重组(HR)和/或分叉保护(FP)中发挥作用。在这里，我们相反地报告说，毒性来自复制差距。BRCA1或FANCJ缺陷细胞具有常见的修复缺陷，但具有不同的PARPI反应，显示缝隙作为区分因素。我们进一步将HR、FP和分叉速度从PARPI响应中分离出来。相反，缺口是BRCA缺陷细胞的特征，在耐药时会减少，在重新敏化时会恢复，当暴露时，会增加PARPI的毒性。未受攻击的BRCA1缺陷细胞多聚(ADP-核糖)和染色质相关的PARP1升高，但XRCC1异常低，这与备份Okazaki片段处理(OFP)中的缺陷一致。53BP1丢失通过恢复XRCC1-LIG3来复苏OFP，XRCC1-LIG3抑制BRCA1缺陷细胞对靶向OFP或产生缺口的药物的敏感性。我们强调GAP是PARPI毒性的决定因素，改变了合成致命相互作用的范式。Cong等人。报告称，复制间隙与PARPI敏感性有关，而DNA修复、分叉保护或分叉速度方面的缺陷可能是分离的，暗示间隙是致敏病变。相应地，间隙抑制与包括BRCA1和53BP1缺乏的细胞在内的抗性完全一致，这些细胞重新开始处理Okazaki片段。
Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded breaks (DSBs) necessitating BRCA function in homologous recombination (HR) and/or fork protection (FP). Here, we report instead that toxicity derives from replication gaps. BRCA1- or FANCJ-deficient cells, with common repair defects but distinct PARPi responses, reveal gaps as a distinguishing factor. We further uncouple HR, FP, and fork speed from PARPi response. Instead, gaps characterize BRCA-deficient cells, are diminished upon resistance, restored upon resensitization, and, when exposed, augment PARPi toxicity. Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP). 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. We highlight gaps as a determinant of PARPi toxicity changing the paradigm for synthetic lethal interactions. Cong et al. report that replication gaps couple with PARPi sensitivity, whereas defects in DNA repair, fork protection, or fork speed can be uncoupled, implicating gaps as the sensitizing lesion. Correspondingly, gap suppression fully aligns with resistance including cells with BRCA1 and 53BP1 deficiency that regain Okazaki fragment processing.
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影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
4
作者：
Ame, Jean-Christophe;Fouquerel, Elise;Schreiber, Valerie
通讯作者：
Schreiber, Valerie
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A