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


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.

Hudson, J.R., Chiang, S., Wells, O.S., Rookyard, C., El-Khamisy, SF (2012). SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Nature Communications, 13; 3:733

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Professor of Molecular Medicine, Director of Research and Innovation and co-founder of the Healthy Life Span Institute, University of Sheffield, United Kingdom

Sherif El-Khamisy is a Wellcome Trust Investigator and co-founder of the Healthy Lifespan Institute at the University of Sheffield. El-Khamisy lab studies how cells maintain genomic integrity and their impact on health. The lab uses interdisciplinary approach fusing genetics, chemistry and biology with clinical expertise. We use mouse and zebrafish models to stay ageing and multimorbidity at the molecular and organismal level. We link our molecular understanding to public health challenges through interactions with social scientists.