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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Werner syndrome protein interacts functionally with translesion DNA polymerases
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Werner syndrome protein interacts functionally with translesion DNA polymerases

机译：Werner综合征蛋白与病灶DNA聚合酶发生功能性相互作用

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摘要

Werner syndrome (WS) is characterized by premature onset of age-associated disorders and predisposition to cancer. The WS protein, WRN, encodes 3' → 5' DNA helicase and 3' → 5' DNA exonuclease activities, and is implicated in the maintenance of genomic stability. Translesion (TLS) DNA polymerases (Pols) insert nucleotides opposite replication-blocking DNA lesions and presumably prevent replication fork stalling/collapse. Here, we present in vitro and in vivo data that demonstrate functional interaction between WRN and the TLS Pols, Polη, Polκ, and Polι. In vitro, WRN stimulates the extension activity of TLS Pols on lesion-free and lesion-containing DNA templates, and alleviates pausing at stalling lesions. Stimulation is mediated through an increase in the apparent V_(max) of the polymerization reaction. Notably, by accelerating the rate of nucleotide incorporation, WRN increases mutagenesis by Polη. In vivo, WRN and Polη colocalize at replication-dependent foci in response to UVC irradiation. The functional interaction between WRN and TLS Pols may promote replication fork progression, at the expense of increased mutagenesis, and obviate the need to resolve stalled/collapsed forks by processes involving chromosomal rearrangements.
机译：Werner综合征（WS）的特征是与年龄相关的疾病过早发作和易患癌症。 WS蛋白WRN编码3'→5'DNA解旋酶和3'→5'DNA核酸外切酶活性，并参与维持基因组稳定性。跨病变（TLS）DNA聚合酶（Pols）在阻止复制的DNA损伤处插入核苷酸，并可能防止复制叉停滞/塌陷。在此，我们提供了体外和体内数据，这些数据证明了WRN与TLS Pols，Polη，Polκ和Polι之间的功能相互作用。在体外，WRN刺激TLS Pols在无病灶和含病灶的DNA模板上的延伸活性，并减轻停滞病灶的停顿。通过聚合反应的表观V_（max）的增加来介导刺激。值得注意的是，通过加快核苷酸掺入速率，WRN增加了Polη的诱变作用。在体内，响应于UVC照射，WRN和Polη共定位在复制依赖性灶上。 WRN和TLS Pols之间的功能相互作用可能会促进复制叉的进展，但会增加诱变作用，并且消除了通过涉及染色体重排的过程解决停滞/折叠叉的需求。

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