Cell-cycle-dependent phosphorylation of RRM1 ensures efficient DNA replication and regulates cancer vulnerability to ATR inhibition.

Abstract

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) building blocks for DNA synthesis, and is a well-recognized target for cancer therapy. RNR is a heterotetramer consisting of two large RRM1 subunits and two small RRM2 subunits. RNR activity is greatly stimulated by transcriptional activation of RRM2 during S/G2 phase to ensure adequate dNTP supply for DNA replication. However, little is known about the cell-cycle-dependent regulation of RNR activity through RRM1. Here, we report that RRM1 is phosphorylated at Ser 559 by CDK2/cyclin A during S/G2 phase. And this S559 phosphorylation of RRM1enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. Defective RRM1 S559 phosphorylation causes DNA replication stress, double-strand break, and genomic instability. Moreover, combined targeting of RRM1 S559 phosphorylation and ATR triggers lethal replication stress and profound antitumor effects. Thus, this posttranslational phosphorylation of RRM1 provides an alternative mechanism to finely regulating RNR and therapeutic opportunities for cancer treatment.

• Authors: Zhen Shu, Zhen Li, Huanhuan Huang, Yan Chen, Jun Fan, Li Yu, Zhihui Wu, Ling Tian, Qi Qi, Shuang Peng, Changyong Wei, Zhongqiu Xie, Xiaobo Li, Qi Feng, Hao Sheng, Guangqiang Li, Dongping Wei, Changliang Shan, Guo Chen
• Journal: Oncogene (Oncogene) Vol. 39 Issue 35 Pg. 5721-5733 (08 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32712628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RRM1 protein, human
• Ribonucleoside Diphosphate Reductase
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors)
• Cell Cycle
• DNA Replication (genetics)
• Humans
• Phosphorylation
• Ribonucleoside Diphosphate Reductase (isolation & purification, metabolism)