TNKS1BP1 functions in DNA double-strand break repair though facilitating DNA-PKcs autophosphorylation dependent on PARP-1.
TNKS1BP1 functions in DNA double-strand break repair though facilitating DNA-PKcs autophosphorylation dependent on PARP-1.
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TNKS1BP1 通过促进依赖于 PARP-1 的 DNA-PKcs 自磷酸化而在 DNA 双链断裂修复中发挥作用
DOI：
10.18632/oncotarget.3137
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发表时间：
2015-03-30
期刊：
影响因子：
--
通讯作者：
Zhou PK
中科院分区：
文献类型：
--
作者：
Zou LH;Shang ZF;Tan W;Liu XD;Xu QZ;Song M;Wang Y;Guan H;Zhang SM;Yu L;Zhong CG;Zhou PK
TNKS 1BP 1最初被鉴定为端锚聚合酶1的相互作用蛋白，端锚聚合酶1属于聚（ADP-核糖）聚合酶（PARP）超家族。PARP成员在例如DNA修复、端粒稳定性和有丝分裂调节中发挥重要作用。虽然TNKS 1BP 1蛋白被认为是端锚聚合酶1的聚（ADP-核糖基）化受体，但其功能仍然未知。本研究首次发现TNKS 1BP 1在电离辐射（IR）诱导下表达上调，TNKS 1BP 1的缺失可使肿瘤细胞对IR产生明显的敏感性，中性彗星实验、脉冲场凝胶电泳和γ H2 AX焦点分析表明TNKS 1BP 1参与了DNA双链断裂（DSB）的有效修复。通过免疫共沉淀分析，TNKS 1BP 1蛋白被证明与DNA依赖性蛋白激酶（DNA-PKcs）和聚（ADP-核糖）聚合酶1（PARP-1）相互作用。此外，TNKS 1BP 1显示促进PARP-1和DNA-PKcs的缔合。TNKS 1BP 1的过表达以PARP-1依赖的方式诱导DNA-PKcs/Ser 2056的自磷酸化，这有助于增强DNA DSB修复能力。抑制PARP-1可阻断TNKS 1BP 1介导的DNA-PKcs的自磷酸化，并减弱DNA-PKcs的PAR化。TNKS 1BP 1是一种新描述的DNA DSB修复机制的组成部分，它为通过靶向PARP-1和DNA-PKcs开发有效的抗癌措施提供了更多的机制证据。
TNKS1BP1 was originally identified as an interaction protein of tankyrase 1, which belongs to the poly(ADP-ribose) polymerase (PARP) superfamily. PARP members play important roles for example in DNA repair, telomere stability and mitosis regulation. Although the TNKS1BP1 protein was considered to be a poly(ADP-ribosyl)ation acceptor of tankyrase 1, its function is still unknown. Here we firstly identified that TNKS1BP1 was up-regulated by ionizing radiation (IR) and the depletion of TNKS1BP1 significantly sensitized cancer cells to IR. Neutral comet assay, pulsed-field gel electrophoresis, and γH2AX foci analysis indicated that TNKS1BP1 is required for the efficient repair of DNA double-strand breaks (DSB). The TNKS1BP1 protein was demonstrated to interact with DNA-dependent protein kinase (DNA-PKcs) and poly(ADP-ribose) polymerase 1 (PARP-1), by co-immunoprecipitation analysis. Moreover, TNKS1BP1 was shown to promote the association of PARP-1 and DNA-PKcs. Overexpression of TNKS1BP1 induced the autophosphorylation of DNA-PKcs/Ser2056 in a PARP-1 dependent manner, which contributed to an increased capability of DNA DSB repair. Inhibition of PARP-1 blocked the TNKS1BP1-mediated DNA-PKcs autophosphorylation and attenuated the PARylation of DNA-PKcs. TNKS1BP1 is a newly described component of the DNA DSB repair machinery, which provides much more mechanistic evidence for the rationale of developing effective anticancer measures by targeting PARP-1 and DNA-PKcs.
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影响因子：
4.8
作者：
Chen, Benjamin P. C.;Uematsu, Naoya;Chen, David J.
通讯作者：
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16
作者：
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14.9
作者：
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通讯作者：
Poirier, Guy G.
影响因子：
14.8
作者：
Sajish, Mathew;Zhou, Quansheng;Kishi, Shuji;Valdez, Delgado M., Jr.;Kapoor, Mili;Guo, Min;Lee, Sunhee;Kim, Sunghoon;Yang, Xiang-Lei;Schimmel, Paul
通讯作者：
Schimmel, Paul