1. The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms.
- Author
-
Garvin AJ, Walker AK, Densham RM, Chauhan AS, Stone HR, Mackay HL, Jamshad M, Starowicz K, Daza-Martin M, Ronson GE, Lanz AJ, Beesley JF, and Morris JR
- Subjects
- Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival radiation effects, Cysteine Endopeptidases genetics, DNA Breaks, Double-Stranded, HEK293 Cells, HeLa Cells, Humans, Infrared Rays, Nuclear Proteins metabolism, Radiation Tolerance genetics, Signal Transduction genetics, Trans-Activators metabolism, Transcription Factors metabolism, Valosin Containing Protein metabolism, Cysteine Endopeptidases metabolism, DNA End-Joining Repair genetics, DNA Repair genetics, Homologous Recombination genetics, Sumoylation genetics
- 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., (© 2019 Garvin et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2019
- Full Text
- View/download PDF