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首页> 外文期刊>Cell cycle >The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome.
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The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome.

机译：DNA修复核酸内切酶XPG与Werner综合征中存在缺陷的WRN解旋酶直接发生功能性相互作用。

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XPG is a structure-specific endonuclease required for nucleotide excision repair (NER). XPG incision defects result in the cancer-prone syndrome xeroderma pigmentosum, whereas truncating mutations of XPG cause the severe postnatal progeroid developmental disorder Cockayne syndrome. We show that XPG interacts directly with WRN protein, which is defective in the premature aging disorder Werner syndrome, and that the two proteins undergo similar subnuclear redistribution in S phase and colocalize in nuclear foci. The co-localization was observed in mid- to late S phase, when WRN moves from nucleoli to nuclear foci that have been shown to contain both protein markers of stalled replication forks and telomeric proteins. We mapped the interaction between XPG and WRN to the C-terminal domains of each, and show that interaction with the C-terminal domain of XPG strongly stimulates WRN helicase activity. WRN also possesses a competing DNA single-strand annealing activity that, combined with unwinding, has been shown to coordinate regression of model replication forks to form Holliday junction/chicken foot intermediate structures. We tested whether XPG stimulated WRN annealing activity, and found that XPG itself has intrinsic strand annealing activity that requires the unstructured R- and C-terminal domains but not the conserved catalytic core or endonuclease activity. Annealing by XPG is cooperative, rather than additive, with WRN annealing. Taken together, our results suggest a novel function for XPG in S phase that is, at least in part, performed coordinately with WRN, and which may contribute to the severity of the phenotypes that occur upon loss of XPG.
机译：XPG是核苷酸切除修复（NER）所需的结构特异性核酸内切酶。 XPG切口缺损会导致易患癌症的色素干皮综合症，而XPG的截短突变会导致严重的产后类胚发育障碍Cockayne综合征。我们显示XPG与WRN蛋白直接相互作用，WRN蛋白在早衰性疾病Werner综合征中存在缺陷，并且这两种蛋白在S期经历相似的亚核再分布并在核灶中共定位。当WRN从核仁转移到核病灶时，在S期的中晚期观察到了共定位，这表明它既包含停滞的复制叉的蛋白标记，又包含端粒蛋白。我们将XPG和WRN之间的相互作用映射到每个C末端域，并显示与XPG的C末端域的相互作用强烈刺激WRN解旋酶活性。 WRN还具有竞争性的DNA单链退火活性，与展开结合，已显示出它可以协调模型复制叉的回归，从而形成霍利迪交界处/鸡足中间结构。我们测试了XPG是否刺激了WRN退火活性，并发现XPG本身具有内在的链退火活性，这需要非结构化的R和C末端结构域，但不需要保守的催化核心或核酸内切酶活性。 XPG退火与WRN退火是协作的，而不是相加的。两者合计，我们的结果表明XPG在S期的一种新功能，至少部分与WRN协同执行，并且可能会导致XPG丢失时出现的表型的严重性。

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