WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells.
WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells.
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DOI：
10.1038/s41467-021-26811-w
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发表时间：
2021-11-12
影响因子：
16.6
通讯作者：
Brosh RM Jr
中科院分区：
文献类型：
--
作者：
Datta A;Biswas K;Sommers JA;Thompson H;Awate S;Nicolae CM;Thakar T;Moldovan GL;Shoemaker RH;Sharan SK;Brosh RM Jr
肿瘤抑制基因BRCA2保护停滞不前的叉子免受退化，以维持基因组的稳定。然而，没有保护的叉子被稳定的分子机制(S)仍然是完全的特征。在这里，我们证明了WRN解旋酶确保了有效的重新启动，并限制了BRCA2缺陷癌细胞中停滞的叉子的过度降解。在体外，WRN ATPase/Helicase催化叉子恢复，并抑制退化叉子上的Mre11核酸酶活性。我们发现WRN解旋酶抑制剂将WRN捕获到染色质上，导致MRE11对未保护的叉子的快速停滞和核溶解降解，导致MUS81依赖的双链断裂，增加非同源末端连接和染色体不稳定性。WRN解旋酶抑制降低BRCA2缺陷细胞的活力，并增强聚(ADP)核糖聚合酶(PARP)抑制剂的细胞毒性。此外，当WRN解旋酶抑制剂治疗时，BRCA2缺陷的小鼠异种移植瘤显示出DNA损伤和生长抑制的增加。这项工作为当BRCA2缺乏时WRN解旋酶稳定失速的叉子提供了机械性的见解。肿瘤抑制因子BRCA2保护停滞的DNA复制叉子不受限制地降解；然而，没有保护的停滞的叉子被保存和重新启动的机制仍然难以捉摸。在这里，作者表明，WRN解旋酶促进停滞的叉子恢复，并在缺乏BRCA2保护的情况下限制叉子的过度降解。
The tumor suppressor BRCA2 protects stalled forks from degradation to maintain genome stability. However, the molecular mechanism(s) whereby unprotected forks are stabilized remains to be fully characterized. Here, we demonstrate that WRN helicase ensures efficient restart and limits excessive degradation of stalled forks in BRCA2-deficient cancer cells. In vitro, WRN ATPase/helicase catalyzes fork restoration and curtails MRE11 nuclease activity on regressed forks. We show that WRN helicase inhibitor traps WRN on chromatin leading to rapid fork stalling and nucleolytic degradation of unprotected forks by MRE11, resulting in MUS81-dependent double-strand breaks, elevated non-homologous end-joining and chromosomal instability. WRN helicase inhibition reduces viability of BRCA2-deficient cells and potentiates cytotoxicity of a poly (ADP)ribose polymerase (PARP) inhibitor. Furthermore, BRCA2-deficient xenograft tumors in mice exhibited increased DNA damage and growth inhibition when treated with WRN helicase inhibitor. This work provides mechanistic insight into stalled fork stabilization by WRN helicase when BRCA2 is deficient. The tumor suppressor BRCA2 protects stalled DNA replication forks from unrestrained degradation; however the mechanism whereby unprotected stalled forks are preserved and restarted has remained elusive. Here the authors show that the WRN helicase promotes stalled fork recovery and limits fork hyper-degradation in the absence of BRCA2 protection.
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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
BRCA2 拮抗经典和替代非同源末端连接以防止基因组总体不稳定
影响因子：
16.6
作者：
Han J;Ruan C;Huen MSY;Wang J;Xie A;Fu C;Liu T;Huang J
通讯作者：
Huang J
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：
16.8
作者：
Bhat KP;Cortez D
通讯作者：
Cortez D