The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms
| Autor: | George E. Ronson, Anoop Singh Chauhan, Alexander J Garvin, Alexandra K. Walker, Hannah L. Mackay, Mohammed Jamshad, Helen R Stone, James F.J. Beesley, Manuel Daza-Martin, Joanna R. Morris, Ruth M Densham, Katarzyna Starowicz, Alexander J. Lanz |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
DNA End-Joining Repair
DNA Repair Cell Survival Infrared Rays DNA repair SUMO protein Cell Cycle Proteins Biology Radiation Tolerance 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Valosin Containing Protein Cell Line Tumor Radioresistance Genetics Humans DNA Breaks Double-Stranded Homologous Recombination Adaptor Proteins Signal Transducing 030304 developmental biology 0303 health sciences RNF4 fungi Nuclear Proteins Sumoylation Cell biology MDC1 Non-homologous end joining Cysteine Endopeptidases enzymes and coenzymes (carbohydrates) HEK293 Cells chemistry 030220 oncology & carcinogenesis Trans-Activators Homologous recombination DNA HeLa Cells Signal Transduction Transcription Factors Research Paper Developmental Biology |
| Zdroj: | Genes & Development. 33:333-347 |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.321125.118 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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