Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.
Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis.
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Poleta O-GlcNAcylation 在跨损伤 DNA 合成过程中控制基因组完整性
DOI：
10.1038/s41467-017-02164-1
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发表时间：
2017-12-05
影响因子：
16.6
通讯作者：
Guo C
中科院分区：
文献类型：
--
作者：
Ma X;Liu H;Li J;Wang Y;Ding YH;Shen H;Yang Y;Sun C;Huang M;Tu Y;Liu Y;Zhao Y;Dong MQ;Xu P;Tang TS;Guo C
DNA聚合酶η(PolDNA聚合酶η)促进紫外线(UV)照射和顺铂诱导的皮肤癌变和耐药表型形成相关的DNA损伤的跨病变DNA合成(TLS)。然而，POLη的翻译后修饰是否参与这些过程在很大程度上尚不清楚。在这里，我们报道了人的POLDNA在η损伤时，通过O-GlcNAc转移酶在苏氨酸457位发生O-GlcN酰化。取消这一修饰导致依赖于CRL4CDT2的POLη在赖氨酸第462位的多泛素化水平降低，依赖于p97的POLη从复制叉处延迟移除，并显著增强UV诱导的突变，即使POLη焦点的形成及其在UV照射后绕过环丁烷嘧啶二聚体的有效性没有受到影响。此外，O-GlcNAc缺陷的T457A突变削弱了TLS绕过顺铂诱导的损伤，导致细胞对顺铂的敏感性增加。我们的发现证明了POLηO-GlcN酰化在TLS调节和基因组稳定性维护中的新作用，并为改进化疗治疗奠定了新的理论基础。POLη是跨损伤DNA合成的关键分子。在这里，作者发现，作为对DNA损伤的响应，POLη在O-GlcNAc转移酶的作用下，在苏氨酸457位进行O-GlcN酰化，以促进DNA损伤旁路后POLη的及时分解。
DNA polymerase η (Polη) facilitates translesion DNA synthesis (TLS) across ultraviolet (UV) irradiation- and cisplatin-induced DNA lesions implicated in skin carcinogenesis and chemoresistant phenotype formation, respectively. However, whether post-translational modifications of Polη are involved in these processes remains largely unknown. Here, we reported that human Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase upon DNA damage. Abrogation of this modification results in a reduced level of CRL4CDT2-dependent Polη polyubiquitination at lysine 462, a delayed p97-dependent removal of Polη from replication forks, and significantly enhanced UV-induced mutagenesis even though Polη focus formation and its efficacy to bypass across cyclobutane pyrimidine dimers after UV irradiation are not affected. Furthermore, the O-GlcNAc-deficient T457A mutation impairs TLS to bypass across cisplatin-induced lesions, causing increased cellular sensitivity to cisplatin. Our findings demonstrate a novel role of Polη O-GlcNAcylation in TLS regulation and genome stability maintenance and establish a new rationale to improve chemotherapeutic treatment. Polη is a key player in translesion DNA synthesis. Here, the authors uncover that, in response to DNA damage, Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase to facilitate the timely disassembly of Polη after DNA lesion bypass.
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DOI：
10.1083/jcb.201008076
发表时间：
2011-01-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Göhler T;Sabbioneda S;Green CM;Lehmann AR
通讯作者：
Lehmann AR
影响因子：
8.8
作者：
Garcia-Exposito L;Bournique E;Bergoglio V;Bose A;Barroso-Gonzalez J;Zhang S;Roncaioli JL;Lee M;Wallace CT;Watkins SC;Opresko PL;Hoffmann JS;O'Sullivan RJ
通讯作者：
O'Sullivan RJ
影响因子：
3.7
作者：
Franz A;Ackermann L;Hoppe T
通讯作者：
Hoppe T
DOI：
10.1084/jem.20050292
发表时间：
2005-04-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Delbos F;De Smet A;Faili A;Aoufouchi S;Weill JC;Reynaud CA
通讯作者：
Reynaud CA
DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA