The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells.
The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells.
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DOI：
10.1101/gad.348479.121
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发表时间：
2021-09-01
影响因子：
10.5
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Simoneau A;Xiong R;Zou L
在这项研究中，西蒙诺等人。研究了为什么 PARPi 在用于治疗 BRCA1/2 缺陷肿瘤时比其他 DNA 损伤药物更有效。他们表明，PARPi 通过跨细胞周期 ssDNA 间隙逐步诱导 DSB，而 BRCA1/2 缺陷细胞无法在多个细胞周期中减慢和修复 DSB，这解释了 PARPi 在 BRCA1/2 缺陷细胞中的独特功效。 PARP 抑制剂 (PARPi) 广泛用于治疗 BRCA1/2 缺陷型肿瘤，但为什么 PARPi 比其他 DNA 损伤药物更有效尚不清楚。在这里，我们证明 PARPi 主要以跨细胞周期的方式产生 DNA 双链断裂 (DSB)。在 PARPi 暴露后的第一个 S 期，PARPi 在 DNA 复制叉后面诱导单链 DNA (ssDNA) 间隙。通过将 PARP 捕获在 DNA 上，PARPi 会阻止间隙修复的完成，直至下一个 S 期，从而导致复制叉与 ssDNA 间隙的碰撞以及 DSB 的激增。在第二个 S 期，BRCA1/2 缺陷细胞无法通过 ATR 抑制起源放电，从而导致持续的 DNA 合成和更多的 DSB。此外，BRCA1/2 缺陷细胞无法招募 RAD51 来修复塌陷的分叉。因此，PARPi 通过跨细胞周期 ssDNA 间隙逐步诱导 DSB，而 BRCA1/2 缺陷细胞无法在多个细胞周期中减缓和修复 DSB，这解释了 PARPi 在 BRCA1/2 缺陷细胞中的独特功效。
In this study, Simoneau et al. investigated why PARPi is more effective than other DNA-damaging drugs when used to treat BRCA1/2-deficient tumors. They show that PARPi induces DSBs progressively through trans-cell-cycle ssDNA gaps, and BRCA1/2-deficient cells fail to slow down and repair DSBs over multiple cell cycles, explaining the unique efficacy of PARPi in BRCA1/2-deficient cells. PARP inhibitor (PARPi) is widely used to treat BRCA1/2-deficient tumors, but why PARPi is more effective than other DNA-damaging drugs is unclear. Here, we show that PARPi generates DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner. During the first S phase after PARPi exposure, PARPi induces single-stranded DNA (ssDNA) gaps behind DNA replication forks. By trapping PARP on DNA, PARPi prevents the completion of gap repair until the next S phase, leading to collisions of replication forks with ssDNA gaps and a surge of DSBs. In the second S phase, BRCA1/2-deficient cells are unable to suppress origin firing through ATR, resulting in continuous DNA synthesis and more DSBs. Furthermore, BRCA1/2-deficient cells cannot recruit RAD51 to repair collapsed forks. Thus, PARPi induces DSBs progressively through trans cell cycle ssDNA gaps, and BRCA1/2-deficient cells fail to slow down and repair DSBs over multiple cell cycles, explaining the unique efficacy of PARPi in BRCA1/2-deficient cells.
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影响因子：
16
作者：
Genois MM;Gagné JP;Yasuhara T;Jackson J;Saxena S;Langelier MF;Ahel I;Bedford MT;Pascal JM;Vindigni A;Poirier GG;Zou L
通讯作者：
Zou L
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：
28.2
作者：
Hill SJ;Decker B;Roberts EA;Horowitz NS;Muto MG;Worley MJ Jr;Feltmate CM;Nucci MR;Swisher EM;Nguyen H;Yang C;Morizane R;Kochupurakkal BS;Do KT;Konstantinopoulos PA;Liu JF;Bonventre JV;Matulonis UA;Shapiro GI;Berkowitz RS;Crum CP;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
16
作者：
Costanzo, V;Shechter, D;Gautier, J
通讯作者：
Gautier, J
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.