Revisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer".
Revisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer".
复制标题
通过复制间隙抑制的透镜重新审视BRCA通路：“间隙决定BRCA突变型癌症的治疗反应”。
DOI：
10.1016/j.dnarep.2021.103209
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发表时间：
2021-11
期刊：
影响因子：
3.8
通讯作者：
Cantor, Sharon B.
中科院分区：
文献类型：
--
作者：
Cantor, Sharon B.
关键词：
针对DNA的化疗产生的毒性病变最初是有争议的，但最终DNA双链断裂（DSB）最终占了上风。部分原因是基于这样一种认知，即修复断裂的染色体需要复杂的过程，否则细胞就会死亡。DSB模型的遗传证据也由DSB修复缺陷细胞的极端敏感性提供。特别是，在遗传性乳腺癌/卵巢癌基因BRCA1或BRCA2中携带突变的细胞具有敏感性，这些基因通过同源重组（HR）修复dsb。除了在HR中的功能外，发现BRCA蛋白通过保护停滞的复制叉免受核酸酶降解来阻止dsb。经过一个完整的循环，对基因毒性化疗产生抗性的BRCA突变癌细胞通常表现出通过HR和/或恢复的叉保护（FP）恢复的DNA修复，这意味着当DSB修复完整或DSB被阻止时，该治疗是耐受的。尽管这种得到充分支持的范式一直是靶向癌症治疗的推动力，但在这里，我们认为导致反应的毒性DNA损伤是单链DNA （ssDNA）缺口。我们讨论的证据表明，在DNA复制后形成的持续的ssDNA间隙，而不是dsb，是基因毒性化疗药物治疗后细胞死亡的原因。我们还强调，已知用于规范DSB修复的蛋白质，如BRCA1， BRCA2和RAD51，在正常复制以及复制间隙抑制（RGS）和修复中也具有关键作用。我们回顾了支持这一观点的文献，即治疗近端广泛的间隙诱导在一个不需要或源于DSB诱导的过程中触发细胞凋亡。最后，我们讨论了空白的临床证据以及如何利用它们来提高基因毒性化疗反应。
The toxic lesion emanating from chemotherapy that targets the DNA was initially debated, but eventually the DNA double strand break (DSB) ultimately prevailed. The reasoning was in part based on the perception that repairing a fractured chromosome necessitated intricate processing or condemned the cell to death. Genetic evidence for the DSB model was also provided by the extreme sensitivity of cells that were deficient in DSB repair. In particular, sensitivity characterized cells harboring mutations in the hereditary breast/ovarian cancer genes, BRCA1 or BRCA2, that function in the repair of DSBs by homologous recombination (HR). Along with functions in HR, BRCA proteins were found to prevent DSBs by protecting stalled replication forks from nuclease degradation. Coming full-circle, BRCA mutant cancer cells that gained resistance to genotoxic chemotherapy often displayed restored DNA repair by HR and/or restored fork protection (FP) implicating that the therapy was tolerated when DSB repair was intact or DSBs were prevented. Despite this well-supported paradigm that has been the impetus for targeted cancer therapy, here we argue that the toxic DNA lesion conferring response is instead single stranded DNA (ssDNA) gaps. We discuss the evidence that persistent ssDNA gaps formed in the wake of DNA replication rather than DSBs are responsible for cell killing following treatment with genotoxic chemotherapeutic agents. We also highlight that proteins, such as BRCA1, BRCA2, and RAD51 known for canonical DSB repair also have critical roles in normal replication as well as replication gap suppression (RGS) and repair. We review the literature that supports the idea that widespread gap induction proximal to treatment triggers apoptosis in a process that does not need or stem from DSB induction. Lastly, we discuss the clinical evidence for gaps and how to exploit them to enhance genotoxic chemotherapy response.
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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：
16.6
作者：
Berti, Matteo;Teloni, Federico;Lopes, Massimo
通讯作者：
Lopes, Massimo
DOI：
10.1073/pnas.1706392114
发表时间：
2017-07-18
影响因子：
11.1
作者：
Chen, Chun-Chin;Kass, Elizabeth M.;Jasin, Maria
通讯作者：
Jasin, Maria
DOI：
10.1073/pnas.1508543112
发表时间：
2015-12-01
影响因子：
11.1
作者：
Belen Vallerga, Maria;Mansilla, Sabrina F.;Gottifredi, Vanesa
通讯作者：
Gottifredi, Vanesa
影响因子：
8.8
作者：
Bhat KP;Krishnamoorthy A;Dungrawala H;Garcin EB;Modesti M;Cortez D
通讯作者：
Cortez D