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Protein kinase ATR inhibits E3 ubiquitin ligase CRL4PRL1 to stabilize ribonucleotide reductase in response to replication stress

文献类型: 外文期刊

作者: Weiyi Bao;Weijia Zhang;Yongchi Huang;Yan Zhao;Cong Wu;Leilei Duan;Lili Wang;Shunping Yan

作者机构:

关键词: ATR;CP: Molecular biology;DNA damage response;DNA replication stress;PRL1;ribonucleotide reductase;TSO2;WEE1

期刊名称: Cell Reports

ISSN: 2211-1247

年卷期: 2023 年 42 卷 7 期

页码:

收录情况: SCIE(2023版)

摘要: The protein kinase ATR is essential for replication stress responses in all eukaryotes. Ribonucleotide reductase (RNR) catalyzes the formation of deoxyribonucleotide (dNTP), the universal building block for DNA replication and repair. However, the relationship between ATR and RNR is not well understood. Here, we show that ATR promotes the protein stability of RNR in Arabidopsis. Through an activation tagging-based genetic screen, we found that overexpression of TSO2, a small subunit of RNR, partially suppresses the hypersensitivity of the atr mutant to replication stress. Biochemically, TSO2 interacts with PRL1, a central subunit of the Cullin4-based E3 ubiquitin ligase CRL4PRL1, which polyubiquitinates TSO2 and promotes its degradation. ATR inhibits CRL4PRL1 to attenuate TSO2 degradation. Our work provides an important insight into the replication stress responses and a post-translational regulatory mechanism for RNR. Given the evolutionary conservation of the proteins involved, the ATR-PRL1-RNR module may act across eukaryotes.

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