XRCC1 counteracts poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib, and a clinical alkylating agent, temozolomide, by promoting the removal of trapped PARP1 from broken DNA.
XRCC1 counteracts poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib, and a clinical alkylating agent, temozolomide, by promoting the removal of trapped PARP1 from broken DNA.
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DOI：
10.1111/gtc.12929
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
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碱基切除修复通过产生单链断裂(SSB)、用DNA聚合酶β(POLβ)填补缺口和重新密封SSB来去除受损的碱基。碱基损伤剂甲烷磺酸甲酯(MMS)被广泛用于BER的研究。BER增加了细胞对MMS、抗癌碱基破坏药物、替莫唑胺、卡莫司汀和洛莫司汀以及临床多聚腺苷二磷酸核糖聚合酶(PARP)毒药、奥拉帕利布和他唑帕利布的耐受性。这些毒物稳定了PARP1/SSB复合体，抑制了BER因子对SSB的访问。PARP1和XRCC1通过将POLβ招募到SSB来协同促进SSB的再密封，但XRCC1−/−细胞比PARP1−/−细胞对MMS更敏感。我们最近报道了XRCC1−/−细胞中PARP1的缺失恢复了其对MMS的耐受性，并得出结论，XPCC1SSB通过维持其自身的PAR化来促进PARP1的释放。我们在这里表明，XRCC1−/−细胞中PARP1的缺失也恢复了它们对三种抗癌碱基损伤药物的耐受性，尽管它们和MMS诱导了不同的碱基损伤。我们揭示了XRCC1−/−突变的合成致死性，而POLβ−/−与奥拉帕利布和他唑巴利布的合成致死性无关，这表明XRCC1是一种独特的抑制PARP1SSB复合体的误码率因子，即使在PARP1催化被抑制的情况下也能抑制。总之，XRCC1通过PARP1催化依赖和独立的机制抑制PARP1/SSB复合体。
Base excision repair (BER) removes damaged bases by generating single‐strand breaks (SSBs), gap‐filling by DNA polymerase β (POLβ), and resealing SSBs. A base‐damaging agent, methyl methanesulfonate (MMS) is widely used to study BER. BER increases cellular tolerance to MMS, anti‐cancer base‐damaging drugs, temozolomide, carmustine, and lomustine, and to clinical poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib. The poisons stabilize PARP1/SSB complexes, inhibiting access of BER factors to SSBs. PARP1 and XRCC1 collaboratively promote SSB resealing by recruiting POLβ to SSBs, but XRCC1 −/− cells are much more sensitive to MMS than PARP1 −/− cells. We recently report that the PARP1 loss in XRCC1 −/− cells restores their MMS tolerance and conclude that XPCC1 facilitates the release of PARP1 from SSBs by maintaining its autoPARylation. We here show that the PARP1 loss in XRCC1 −/− cells also restores their tolerance to the three anti‐cancer base‐damaging drugs, although they and MMS induce different sets of base damage. We reveal the synthetic lethality of the XRCC1 −/− mutation, but not POLβ −/−, with olaparib and talazoparib, indicating that XRCC1 is a unique BER factor in suppressing toxic PARP1/SSB complex and can suppress even when PARP1 catalysis is inhibited. In conclusion, XRCC1 suppresses the PARP1/SSB complex via PARP1 catalysis‐dependent and independent mechanisms.
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影响因子：
5.3
作者：
CALDECOTT, KW;MCKEOWN, CK;THOMPSON, LH
通讯作者：
THOMPSON, LH
DOI：
10.1073/pnas.0914077107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Cuneo, Matthew J.;London, Robert E.
通讯作者：
London, Robert E.
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
通过双重抑制NAD+生物合成和碱基切除修复，克服胶质母细胞瘤中替莫唑胺的耐药性。
影响因子：
11.2
作者：
Goellner EM;Grimme B;Brown AR;Lin YC;Wang XH;Sugrue KF;Mitchell L;Trivedi RN;Tang JB;Sobol RW
通讯作者：
Sobol RW
影响因子：
14.9
作者：
El-Khamisy, SF;Masutani, M;Caldecott, KW
通讯作者：
Caldecott, KW