title: SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair.
abstract: Breaking and sealing one strand of DNA is an inherent feature of chromosome metabolism to overcome torsional barriers. Failure to reseal broken DNA strands results in protein-linked DNA breaks, causing neurodegeneration in humans. This is typified by defects in tyrosyl DNA phosphodiesterase 1 (TDP1), which removes stalled topoisomerase 1 peptides from DNA termini. Here we show that TDP1 is a substrate for modification by the small ubiquitin-like modifier SUMO. We purify SUMOylated TDP1 from mammalian cells and identify the SUMOylation site as lysine 111. While SUMOylation exhibits no impact on TDP1 catalytic activity, it promotes its accumulation at sites of DNA damage. A TDP1 SUMOylation-deficient mutant displays a reduced rate of repair of chromosomal single-strand breaks arising from transcription-associated topoisomerase 1 activity or oxidative stress. These data identify a role for SUMO during single-strand break repair, and suggest a mechanism for protecting the nervous system from genotoxic stress.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Jessica J R
authors.initials: JJ
authors.lastname: Hudson
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chiang
authors.forename: Owen S
authors.initials: OS
authors.lastname: Wells
authors.forename: Chris
authors.initials: C
authors.lastname: Rookyard
authors.forename: Sherif F
authors.initials: SF
authors.lastname: El-Khamisy
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D018384:Oxidative Stress; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: D050505:Mutant Proteins; D025842:SUMO-1 Protein; D049452:Green Fluorescent Proteins; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I