The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1
The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1
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DOI：
10.1074/jbc.m703343200
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发表时间：
2007-09-07
影响因子：
4.8
通讯作者：
Bohr, Vilhelm A.
中科院分区：
文献类型：
--
作者：
Das, Aditi;Boldogh, Istvan;Bohr, Vilhelm A.
哺乳动物DNA糖基化酶NEIL 1通过碱基切除修复途径特异性修复基因组中的氧化损伤碱基，可被活性氧激活并防止辐射引起的毒性。在这里，我们表明，沃纳综合征蛋白（WRN），RecQ家族的DNA解旋酶的成员，与NEIL 1在早期的碱基切除修复的损伤传感步骤。WRN刺激NEIL 1从气泡DNA底物中切除氧化损伤。NEIL 1和WRN之间的二元相互作用（KD = 60 nM）涉及NEIL 1的C-末端残基288-349和WRN的RecQ C-末端（RQC）区域，并且不依赖于解旋酶活性WRN。暴露于氧化应激增强NEIL-WRN协会伴随着他们强大的核共定位。WRN耗尽的细胞积累一些原型氧化碱基（例如，G. 8-氧代鸟嘌呤、FapyG和FapyA），表明WRN在哺乳动物基因组中的氧化损伤修复中的生理功能。有趣的是，WRN缺陷对NEIL 1敲除细胞中的体内损伤累积没有累加效应，表明WRN参与与NEIL 1相同的修复途径。
The mammalian DNA glycosylase, NEIL1, specific for repair of oxidatively damaged bases in the genome via the base excision repair pathway, is activated by reactive oxygen species and prevents toxicity due to radiation. We show here that the Werner syndrome protein (WRN), a member of the RecQ family of DNA helicases, associates with NEIL1 in the early damage-sensing step of base excision repair. WRN stimulates NEIL1 in excision of oxidative lesions from bubble DNA substrates. The binary interaction between NEIL1 and WRN (K-D = 60 nM) involves C-terminal residues 288-349 of NEIL1 and the RecQ C-terminal (RQC) region of WRN, and is independent of the helicase activity WRN. Exposure to oxidative stress enhances the NEIL-WRN association concomitant with their strong nuclear co-localization. WRN-depleted cells accumulate some prototypical oxidized bases (e. g. 8-oxoguanine, FapyG, and FapyA) indicating a physiological function of WRN in oxidative damage repair in mammalian genomes. Interestingly, WRN deficiency does not have an additive effect on in vivo damage accumulation in NEIL1 knockdown cells suggesting that WRN participates in the same repair pathway as NEIL1.