Journal Article

SUMO-targeted ubiquitin ligase activity can either suppress or promote genome instability, depending on the nature of the DNA lesion

Boddy, Michael N., Nie, Minghua, Nakamura, Toru M., Moser, Bettina A.

2017

Overview

The posttranslational modifiers SUMO and ubiquitin critically regulate the DNA damage response (DDR). Important crosstalk between these modifiers at DNA lesions is mediated by the SUMO-targeted ubiquitin ligase (STUbL), which ubiquitinates SUMO chains to generate SUMO-ubiquitin hybrids. These SUMO-ubiquitin hybrids attract DDR proteins able to bind both modifiers, and/or are degraded at the proteasome. Despite these insights, specific roles for SUMO chains and STUbL in the DDR remain poorly defined. Notably, fission yeast defective in SUMO chain formation exhibit near wild-type resistance to genotoxins and moreover, have a greatly reduced dependency on STUbL activity for DNA repair. Based on these and other data, we propose that a critical role of STUbL is to antagonize DDR-inhibitory SUMO chain formation at DNA lesions. In this regard, we identify a SUMO-binding Swi2/Snf2 translocase called Rrp2 (ScUls1) as a mediator of the DDR defects in STUbL mutant cells. Therefore, in support of our proposal, SUMO chains attract activities that can antagonize STUbL and other DNA repair factors. Finally, we find that Taz1TRF1/TRF2-deficiency triggers extensive telomeric poly-SUMOylation. In this setting STUbL, together with its cofactor Cdc48p97, actually promotes genomic instability caused by the aberrant processing of taz1Δ telomeres by DNA repair factors. In summary, depending on the nature of the initiating DNA lesion, STUbL activity can either be beneficial or harmful.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine Triphosphatases - genetics / Adenosine Triphosphatases - metabolism / Analysis / Biochemistry / Biology and life sciences / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell development (Biology) / Chromosomal Proteins, Non-Histone - genetics / Chromosomal Proteins, Non-Histone - metabolism / Defects / Deoxyribonucleic acid / DNA / DNA damage / DNA Repair / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Embryonic development / Fission / Genetic aspects / Genetics / Genome, Fungal / Genomes / Genomic Instability / Hybrids / Lesions / Physical Sciences / Proteasomes / Proteins / Research and Analysis Methods / Research centers / Schizosaccharomyces - genetics / Schizosaccharomyces - metabolism / Schizosaccharomyces pombe Proteins - genetics / Schizosaccharomyces pombe Proteins - metabolism / Small Ubiquitin-Related Modifier Proteins - genetics / Small Ubiquitin-Related Modifier Proteins - metabolism / SUMO protein / Sumoylation / Telomerase / Telomere-binding protein / Telomere-Binding Proteins - genetics / Telomere-Binding Proteins - metabolism / Transcription (Genetics) / Translocase / TRF2 protein / Ubiquitin-proteasome system / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Valosin Containing Protein / Yeast