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.
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Acknowledgements
We are grateful to Stephanie Jamison for the English editing.
Funding
This work was supported by Natural Science Foundation of Guangdong Province of China (2019A1515011247 to GC), Guangzhou Municipal Science and Technology Program of China (202002030451 to GC), Fundamental Research Funds for the Central Universities (21620421 to GC) and National Natural Science Foundation of China (81472793 and 81672895 to DW).
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Shu, Z., Li, Z., Huang, H. et al. Cell-cycle-dependent phosphorylation of RRM1 ensures efficient DNA replication and regulates cancer vulnerability to ATR inhibition. Oncogene 39, 5721–5733 (2020). https://doi.org/10.1038/s41388-020-01403-y
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DOI: https://doi.org/10.1038/s41388-020-01403-y
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