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SUMO-targeted ubiquitin ligase, Rad60, and Nse2 SUMO ligase suppress spontaneous Top1-mediated DNA damage and genome instability

Publication Type : Journal Article

Publisher : PLoS Genetics

Source : PLoS Genetics, Volume 7, Number 3 (2011)

Keywords : article, cell cycle arrest, cell cycle S phase, Cell death, cell metabolism, chromatin immunoprecipitation, Chromosomal Proteins, controlled study, deoxyribonuclease, DNA adduct, DNA Adducts, DNA damage, DNA repair, DNA topoisomerase, DNA Topoisomerases, enzyme activity, epistasis, fungal protein, Fungal Proteins, genetic recombination, genetic stability, genetics, genomic instability, metabolism, Non-Histone, nonhistone protein, nonhuman, Nse2 protein, phosphodiesterase, phosphodiesterase I, Phosphoric Diester Hydrolases, polymerase chain reaction, protein, protein rad16, protein Rad60, protein Swi10, RAD16 protein, Rad60 protein, S pombe, Schizosaccharomyces, Schizosaccharomyces pombe protein, Schizosaccharomyces pombe Proteins, Schizosaccharomycetaceae, signal transduction, SUMO 1 protein, SUMO E3 ligase Nse2, SUMO targeted ubiquitin ligase, SUMO-1 Protein, Tdp1 protein, Type I, tyrosyl DNA phosphodiesterase I, ubiquitin protein ligase, Ubiquitin-Protein Ligases, unclassified drug

Campus : Amritapuri

School : School of Biotechnology

Department : biotechnology

Year : 2011

Abstract : Through as yet undefined proteins and pathways, the SUMO-targeted ubiquitin ligase (STUbL) suppresses genomic instability by ubiquitinating SUMO conjugated proteins and driving their proteasomal destruction. Here, we identify a critical function for fission yeast STUbL in suppressing spontaneous and chemically induced topoisomerase I (Top1)-mediated DNA damage. Strikingly, cells with reduced STUbL activity are dependent on tyrosyl-DNA phosphodiesterase 1 (Tdp1). This is notable, as cells lacking Tdp1 are largely aphenotypic in the vegetative cell cycle due to the existence of alternative pathways for the removal of covalent Top1-DNA adducts (Top1cc). We further identify Rad60, a SUMO mimetic and STUbL-interacting protein, and the SUMO E3 ligase Nse2 as critical Top1cc repair factors in cells lacking Tdp1. Detection of Top1ccs using chromatin immunoprecipitation and quantitative PCR shows that they are elevated in cells lacking Tdp1 and STUbL, Rad60, or Nse2 SUMO ligase activity. These unrepaired Top1ccs are shown to cause DNA damage, hyper-recombination, and checkpoint-mediated cell cycle arrest. We further determine that Tdp1 and the nucleotide excision repair endonuclease Rad16-Swi10 initiate the major Top1cc repair pathways of fission yeast. Tdp1-based repair is the predominant activity outside S phase, likely acting on transcription-coupled Top1cc. Epistasis analyses suggest that STUbL, Rad60, and Nse2 facilitate the Rad16-Swi10 pathway, parallel to Tdp1. Collectively, these results reveal a unified role for STUbL, Rad60, and Nse2 in protecting genome stability against spontaneous Top1-mediated DNA damage. © 2011 Heideker et al.

Cite this Research Publication : Ja Heideker, Prudden, Ja, Perry, J. J. Pab, Tainer, J. Aac, and Boddy, M. Na, “SUMO-targeted ubiquitin ligase, Rad60, and Nse2 SUMO ligase suppress spontaneous Top1-mediated DNA damage and genome instability”, PLoS Genetics, vol. 7, 2011.

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