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EMBO J. 2019 Apr 15;38(8). pii: e101496. doi: 10.15252/embj.2019101496. Epub 2019 Mar 26.

SUMOylation promotes protective responses to DNA-protein crosslinks.

Author information

1
Ubiquitin Signaling Group, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
2
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
3
Department of Molecular Genetics, Oncode Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
4
Ubiquitin Signaling Group, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark niels.mailand@cpr.ku.dk.
5
Center for Chromosome Stability, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Abstract

DNA-protein crosslinks (DPCs) are highly cytotoxic lesions that obstruct essential DNA transactions and whose resolution is critical for cell and organismal fitness. However, the mechanisms by which cells respond to and overcome DPCs remain incompletely understood. Recent studies unveiled a dedicated DPC repair pathway in higher eukaryotes involving the SprT-type metalloprotease SPRTN/DVC1, which proteolytically processes DPCs during DNA replication in a ubiquitin-regulated manner. Here, we show that chemically induced and defined enzymatic DPCs trigger potent chromatin SUMOylation responses targeting the crosslinked proteins and associated factors. Consequently, inhibiting SUMOylation compromises DPC clearance and cellular fitness. We demonstrate that ACRC/GCNA family SprT proteases interact with SUMO and establish important physiological roles of Caenorhabditis elegans GCNA-1 and SUMOylation in promoting germ cell and embryonic survival upon DPC formation. Our findings provide first global insights into signaling responses to DPCs and reveal an evolutionarily conserved function of SUMOylation in facilitating responses to these lesions in metazoans that may complement replication-coupled DPC resolution processes.

KEYWORDS:

SUMO ; DNA repair; DNA‐protein crosslinks; post‐translational modifications; proteomics

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