The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

Genes & Development
Alexander J GarvinJoanna R Morris

Abstract

SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2. We found that regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast, we show that HR is differentially sensitive to SUMO availability and SENP2 activity is needed to provide SUMO. SENP2 is amplified as part of the chromosome 3q amplification in many cancers. Increased SENP2 expression prolongs MDC1 focus retention and increases NHEJ and radioresistance. Collectively, our data reveal that deSUMOylation differentially primes cells for responding to DSBs and demonstrates the ability of SENP2 to tune DSB repair responses.

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Citations

Jun 25, 2020·Signal Transduction and Targeted Therapy·Liwen ZhouTiebang Kang
Apr 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Qiaoyu LinChuanmao Zhang
Jan 31, 2020·Frontiers in Cell and Developmental Biology·Jan Keiten-SchmitzStefan Müller
Mar 19, 2020·Critical Reviews in Biochemistry and Molecular Biology·Andrea Rabellino, Kum Kum Khanna
May 1, 2021·Cancers·Paulina Tokarz, Katarzyna Woźniak
Jun 3, 2021·International Journal of Molecular Sciences·Ya-Chu ChangAnja-Katrin Bielinsky
Aug 2, 2021·Current Opinion in Genetics & Development·Nalini Dhingra, Xiaolan Zhao
Oct 11, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Yuhong ZhangYitao Qi

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