RB Regulates DNA Double Strand Break Repair Pathway Choice by Mediating CtIP Dependent End Resection.
RB Regulates DNA Double Strand Break Repair Pathway Choice by Mediating CtIP Dependent End Resection.
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DOI：
10.3390/ijms21239176
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发表时间：
2020-12-01
影响因子：
5.6
通讯作者：
Chu WK
中科院分区：
文献类型：
--
作者：
Jiang Y;Yam JC;Tham CC;Pang CP;Chu WK
视网膜母细胞瘤肿瘤抑制基因（RB1）失活导致基因组不稳定，并且可以在视网膜母细胞瘤和其他癌症中检测到。DNA双链断裂（DSB）可通过同源重组（HR）、经典非同源末端连接（C-NHEJ）和微同源介导末端连接（MMEJ）修复。我们旨在研究RB在调节多种DSB修复途径中的机制作用。我们发现HR和C-NHEJ减少，但MMEJ在rb耗尽的细胞中升高。喜树碱诱导DSB后，RB与CtIP共定位，调控DSB末端切除。RB耗竭导致RPA和原生BrdU灶减少，这意味着末端切除减少。在rb缺失的细胞中，观察到较少的CtIP病灶，并且CtIP Thr847缺乏磷酸化。根据合成致死性原理，基于改变DSB修复途径的选择，喜树碱诱导DSB后，RB缺失细胞对喜树碱和MMEJ阻断剂聚adp核糖聚合酶1 （PARP1）抑制剂共同处理更为敏感。我们提出了一个模型，其中RB可以通过介导CtIP依赖的DNA末端切除来调节DSB修复途径的选择。使用PARP1抑制剂可能潜在地改善rb缺陷癌症的治疗结果。
Inactivation of the retinoblastoma tumor suppressor gene (RB1) leads to genome instability, and can be detected in retinoblastoma and other cancers. One damaging effect is causing DNA double strand breaks (DSB), which, however, can be repaired by homologous recombination (HR), classical non-homologous end joining (C-NHEJ), and micro-homology mediated end joining (MMEJ). We aimed to study the mechanistic roles of RB in regulating multiple DSB repair pathways. Here we show that HR and C-NHEJ are decreased, but MMEJ is elevated in RB-depleted cells. After inducing DSB by camptothecin, RB co-localizes with CtIP, which regulates DSB end resection. RB depletion leads to less RPA and native BrdU foci, which implies less end resection. In RB-depleted cells, less CtIP foci, and a lack of phosphorylation on CtIP Thr847, are observed. According to the synthetic lethality principle, based on the altered DSB repair pathway choice, after inducing DSBs by camptothecin, RB depleted cells are more sensitive to co-treatment with camptothecin and MMEJ blocker poly-ADP ribose polymerase 1 (PARP1) inhibitor. We propose a model whereby RB can regulate DSB repair pathway choice by mediating the CtIP dependent DNA end resection. The use of PARP1 inhibitor could potentially improve treatment outcomes for RB-deficient cancers.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
11.4
作者：
Aylon, Y;Liefshitz, B;Kupiec, M
通讯作者：
Kupiec, M
影响因子：
14.9
作者：
Ahrabi S;Sarkar S;Pfister SX;Pirovano G;Higgins GS;Porter AC;Humphrey TC
通讯作者：
Humphrey TC
DOI：
10.1083/jcb.201401146
发表时间：
2014-09-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Barton O;Naumann SC;Diemer-Biehs R;Künzel J;Steinlage M;Conrad S;Makharashvili N;Wang J;Feng L;Lopez BS;Paull TT;Chen J;Jeggo PA;Löbrich M
通讯作者：
Löbrich M
影响因子：
4.4
作者：
Fusco, C;Reymond, A;Zervos, AS
通讯作者：
Zervos, AS