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

Zhen Shu1,2, Zhen Li1,3, Huanhuan Huang4

  • 1Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, China.

Oncogene
|July 27, 2020
PubMed

Insights

Researchers discovered that phosphorylating Ribonucleotide reductase (RNR) subunit RRM1 at Serine 559 enhances DNA synthesis. This finding reveals a new mechanism for regulating RNR activity and offers novel cancer therapy strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Ribonucleotide reductase (RNR) is crucial for DNA synthesis and a cancer therapy target.
  • RNR activity is regulated by its subunits RRM1 and RRM2, with RRM2 regulation well-studied.
  • Cell-cycle-dependent regulation of RNR via RRM1 remains largely unknown.

Purpose of the Study:

  • To investigate the cell-cycle-dependent regulation of RNR activity through its RRM1 subunit.
  • To identify posttranslational modifications of RRM1 and their functional consequences.

Main Methods:

  • Phosphorylation site mapping of RRM1.
  • Enzymatic activity assays.
  • Cell-cycle analysis and DNA replication stress studies.

Main Results:

  • RRM1 is phosphorylated at Serine 559 (S559) by CDK2/cyclin A during the S/G2 phase.
  • S559 phosphorylation enhances RNR enzymatic activity, ensuring sufficient deoxyribonucleotide triphosphates (dNTPs) for DNA replication.
  • Impaired RRM1 S559 phosphorylation leads to replication stress, DNA double-strand breaks, and genomic instability.
  • Targeting RRM1 S559 phosphorylation with ATR inhibitors induces lethal replication stress and significant antitumor effects.

Conclusions:

  • Posttranslational phosphorylation of RRM1 at S559 is a key mechanism for regulating RNR activity during the cell cycle.
  • This regulation is essential for maintaining genomic stability.
  • Targeting RRM1 S559 phosphorylation presents a promising therapeutic strategy for cancer treatment.

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