Acetylation regulates ribonucleotide reductase activity and cancer cell growth

• Type of Material: Article
• Authors: Guo Chen, Emory University; Yin Luo, Emory University; Kurt Warncke, Emory University; Youwei Sun, Emory University; David Yu, Emory University; Haian Fu, Emory University; Madhusmita Behera, Emory University; Suresh S Ramalingam, Emory University; Paul Doetsch, Emory University; Duc M. Duong, Emory University; Michael Lammers, University of Greifswald; Walter J Curran, Emory University; Xingming Deng, Emory University
• Language: English
• Date: 2019-07-19
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-019-11214-9
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 10
• Issue: 1
• Start Page: 3213
• End Page: 3213
• Grant/Funding Information: This work was supported by NIH/NCI grants R01CA193828, R01CA136534 and R01CA200905–01A1 (to X. Deng); by U01CA217875 (to H. Fu); by 5R01DK054514 (to K. Warncke); by R01CA178999 (to D.S.Y.); by NIH Intramural Research Program Projects Z1AES103328 (to P.W.D.) and Z1AES103266 (to P.W.D.); by the Winship Research Informatics, Pathology and Integrated Cellular Imaging shared resource; the cores supported by the Winship Cancer Institute of Emory University (P30CAJ 38292); by the Winship Fashion a Cure Research Scholar Award (to X. Deng); a philanthropic award provided by the Winship Cancer Institute of Emory University; and by Winship Endowment Fund (to X. Deng).
• Keywords: CHECKPOINT; REPLICATION STRESS; DNA-REPLICATION; Multidisciplinary Sciences; DEACETYLATION; GENOME INTEGRITY; Science & Technology; ATR; P53; PHOSPHORYLATION; DEGRADATION; Science & Technology - Other Topicso; DAMAGE
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology; Chemistry, Biochemistry

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.