CDK2 phosphorylation of Werner protein (WRN) contributes to WRN’s DNA double-strand break repair pathway choice,Aging Cell

当前位置： X-MOL 学术 › Aging Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

CDK2 phosphorylation of Werner protein (WRN) contributes to WRN’s DNA double-strand break repair pathway choice
Aging Cell ( IF 8.0 ) Pub Date : 2021-10-06 , DOI: 10.1111/acel.13484
Jong-Hyuk Lee ₁ , Raghavendra A Shamanna ₁ , Tomasz Kulikowicz ₁ , Nima Borhan Fakouri ₁ , Edward W Kim ₁ , Louise S Christiansen ₁ , Deborah L Croteau ₁ , Vilhelm A Bohr _{1,

2}

Affiliation

Werner syndrome (WS) is an accelerated aging disorder characterized by genomic instability, which is caused by WRN protein deficiency. WRN participates in DNA metabolism including DNA repair. In a previous report, we showed that WRN protein is recruited to laser-induced DNA double-strand break (DSB) sites during various stages of the cell cycle with similar intensities, supporting that WRN participates in both non-homologous end joining (NHEJ) and homologous recombination (HR). Here, we demonstrate that the phosphorylation of WRN by CDK2 on serine residue 426 is critical for WRN to make its DSB repair pathway choice between NHEJ and HR. Cells expressing WRN engineered to mimic the unphosphorylated or phosphorylation state at serine 426 showed abnormal DSB recruitment, altered RPA interaction, strand annealing, and DSB repair activities. The CDK2 phosphorylation on serine 426 stabilizes WRN’s affinity for RPA, likely increasing its long-range resection at the end of DNA strands, which is a crucial step for HR. Collectively, the data shown here demonstrate that a CDK2-dependent phosphorylation of WRN regulates DSB repair pathway choice and cell cycle participation.

中文翻译：

Werner 蛋白 (WRN) 的 CDK2 磷酸化有助于 WRN 的 DNA 双链断裂修复途径选择

Werner 综合征 (WS) 是一种加速衰老的疾病，其特征是基因组不稳定，这是由 WRN 蛋白缺乏引起的。WRN 参与 DNA 代谢，包括 DNA 修复。在之前的一份报告中，我们发现 WRN 蛋白在细胞周期的不同阶段以相似的强度被招募到激光诱导的 DNA 双链断裂 (DSB) 位点，支持 WRN 参与非同源末端连接 (NHEJ)和同源重组（HR）。在这里，我们证明 CDK2 对丝氨酸残基 426 的 WRN 磷酸化对于 WRN 在 NHEJ 和 HR 之间选择其 DSB 修复途径至关重要。表达 WRN 的细胞经过工程改造以模拟丝氨酸 426 处的未磷酸化或磷酸化状态，显示出异常的 DSB 募集、改变的 RPA 相互作用、链退火和 DSB 修复活动。丝氨酸 426 上的 CDK2 磷酸化稳定了 WRN 对 RPA 的亲和力，可能会增加其在 DNA 链末端的远距离切除，这是 HR 的关键步骤。总的来说，此处显示的数据表明 WRN 的 CDK2 依赖性磷酸化调节 DSB 修复途径选择和细胞周期参与。

更新日期：2021-11-13

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南