SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair

• Published in: Nature communications Vol. 3; no. 1; p. 733
• Main Authors: Hudson, Jessica J.R., Chiang, Shih-Chieh, Wells, Owen S., Rookyard, Chris, El-Khamisy, Sherif F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2012; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/337/1427/2123; 631/337/458/538; 631/378/1689/364; Antibodies; Binding Sites; Cell Line; DNA Breaks, Single-Stranded; DNA Damage; DNA Repair; DNA Topoisomerases, Type I - genetics; DNA Topoisomerases, Type I - metabolism; Experiments; Green Fluorescent Proteins; HEK293 Cells; Humanities and Social Sciences; Humans; Kinases; multidisciplinary; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutation; Neurodegenerative Diseases - metabolism; Oxidative Stress; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Phosphorylation; Proteins; Science; Science (multidisciplinary); SUMO-1 Protein - metabolism; Sumoylation; Transcription, Genetic; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms1739

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. Tyrosyl DNA phosphodiesterase 1 (TDP1) repairs DNA breaks and is mutated in the disease Spinocerebellar Ataxia with Axonal Neuropathy. Here TDP1 is shown to be post-translationally modified by sumoylation of lysine 111, and cells carrying a mutation at this residue are inefficient at single-strand DNA break repair.