PT  - JOURNAL ARTICLE
AU  - Alexander J. Garvin
AU  - Alexandra K. Walker
AU  - Ruth M. Densham
AU  - Anoop Singh Chauhan
AU  - Helen R. Stone
AU  - Hannah L. Mackay
AU  - Mohammed Jamshad
AU  - Katarzyna Starowicz
AU  - Manuel Daza-Martin
AU  - Joanna R. Morris
TI  - The deSUMOylase SENP2 coordinates homologous recombination and non-homologous end joining by independent mechanisms
AID  - 10.1101/473991
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 473991
4099  - http://biorxiv.org/content/early/2018/11/28/473991.short
4100  - http://biorxiv.org/content/early/2018/11/28/473991.full
AB  - SUMOylation 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 non-homologous enjoining (NHEJ) through the investigation of the deSUMOylase SENP2. We find regulated deSUMOylation of MDC1 prevents excessive SUMOylation and its RNF4-VCP mediated clearance from DSBs, thereby promoting NHEJ. In contrast we show 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 foci 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.