XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
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DOI：
10.1016/j.molcel.2021.05.009
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发表时间：
2021-07-15
期刊：
影响因子：
16
通讯作者：
Caldecott KW
中科院分区：
文献类型：
--
作者：
Demin AA;Hirota K;Tsuda M;Adamowicz M;Hailstone R;Brazina J;Gittens W;Kalasova I;Shao Z;Zha S;Sasanuma H;Hanzlikova H;Takeda S;Caldecott KW
哺乳动物DNA碱基切除修复（BER）由聚（ADP-核糖）聚合酶（PARP）和支架蛋白XRCC 1加速。PARP是检测单链断裂中间体的传感器，但XRCC 1在BER过程中的关键作用尚不清楚。在这里，我们表明，含有DNA聚合酶β和DNA连接酶III的蛋白质复合物由XRCC 1组装，防止BER期间PARP 1的过度参与和活性。因此，PARP 1以类似于PARP抑制剂诱导的方式被“捕获”在XRCC 1缺陷细胞中的BER中间体上，包括在来自XRCC 1突变疾病的患者成纤维细胞中。这种过度的PARP 1参与和捕获使得BER中间体无法被DNA聚合酶β等酶所接近，并阻碍了它们的修复。因此，PARP 1缺失拯救了BER和对XRCC 1 −/−细胞中碱基损伤的抵抗力。这些数据揭示了BER过程中过度的PARP 1参与对基因组完整性的威胁，并将XRCC 1鉴定为防止有毒PARP 1活性的“反陷阱”。DNA碱基切除修复过程中，XRCC 1阻止内源性PARP 1捕获PARP 1捕获阻碍碱基切除修复并增加对碱基损伤的敏感性。显示了在DNA碱基切除修复过程中支架蛋白XRCC 1的基本作用是防止PARP 1在SSB中间体上的毒性“捕获”，否则其会阻断该基本修复过程并导致细胞对DNA碱基损伤的敏感性增加。
Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase β and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes “trapped” on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1−/− cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an “anti-trapper” that prevents toxic PARP1 activity. XRCC1 prevents endogenous PARP1 trapping during DNA base excision repair PARP1 trapping impedes base excision repair and increases sensitivity to base damage In the absence of PARP1, XRCC1 is dispensable for DNA base excision repair Demin et al. show that the essential role of the scaffold protein XRCC1 during DNA base excision repair is to prevent toxic “trapping” of PARP1 on SSB intermediates, which otherwise block this essential repair process and lead to increased cellular sensitivity to DNA base damage.
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影响因子：
14.9
作者：
Hanzlikova H;Gittens W;Krejcikova K;Zeng Z;Caldecott KW
通讯作者：
Caldecott KW
影响因子：
5.3
作者：
CALDECOTT, KW;MCKEOWN, CK;THOMPSON, LH
通讯作者：
THOMPSON, LH
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
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.
影响因子：
14.9
作者：
El-Khamisy, SF;Masutani, M;Caldecott, KW
通讯作者：
Caldecott, KW