Acetylation regulates ribonucleotide reductase activity and cancer cell growth

Guo Chen, Yin Luo, Kurt Warncke, Youwei Sun, David S. Yu, Haian Fu, Madhusmita Behera, Suresh S. Ramalingam, Paul W. Doetsch, Duc M. Duong, Michael Lammers, Walter J. Curran and Xingming Deng ()
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Guo Chen: Emory University School of Medicine and Winship Cancer Institute of Emory University
Yin Luo: Emory University School of Medicine and Winship Cancer Institute of Emory University
Kurt Warncke: Emory University
Youwei Sun: Emory University School of Medicine and Winship Cancer Institute of Emory University
David S. Yu: Emory University School of Medicine and Winship Cancer Institute of Emory University
Haian Fu: Emory University School of Medicine and Winship Cancer Institute of Emory University
Madhusmita Behera: Emory University School of Medicine and Winship Cancer Institute of Emory University
Suresh S. Ramalingam: Emory University School of Medicine and Winship Cancer Institute of Emory University
Paul W. Doetsch: National Institutes of Health
Duc M. Duong: Emory University School of Medicine
Michael Lammers: University of Greifswald
Walter J. Curran: Emory University School of Medicine and Winship Cancer Institute of Emory University
Xingming Deng: Emory University School of Medicine and Winship Cancer Institute of Emory University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates (dNDPs) to provide dNTP precursors for DNA synthesis. Here, we report that acetylation and deacetylation of the RRM2 subunit of RNR acts as a molecular switch that impacts RNR activity, dNTP synthesis, and DNA replication fork progression. Acetylation of RRM2 at K95 abrogates RNR activity by disrupting its homodimer assembly. RRM2 is directly acetylated by KAT7, and deacetylated by Sirt2, respectively. Sirt2, which level peak in S phase, sustains RNR activity at or above a threshold level required for dNTPs synthesis. We also find that radiation or camptothecin-induced DNA damage promotes RRM2 deacetylation by enhancing Sirt2–RRM2 interaction. Acetylation of RRM2 at K95 results in the reduction of the dNTP pool, DNA replication fork stalling, and the suppression of tumor cell growth in vitro and in vivo. This study therefore identifies acetylation as a regulatory mechanism governing RNR activity.

Date: 2019
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DOI: 10.1038/s41467-019-11214-9

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