SUMOylation promotes protective responses to DNA-protein crosslinks.
Nikoline BorgermannLeena AckermannPetra SchwertmanIvo A HendriksKaren ThijssenJulio Cy LiuHannes LansMichael L NielsenNiels MailandPublished in: The EMBO journal (2019)
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.
Keyphrases
- single molecule
- circulating tumor
- cell free
- physical activity
- transcription factor
- germ cell
- body composition
- induced apoptosis
- single cell
- gene expression
- signaling pathway
- stem cells
- hydrogen peroxide
- small molecule
- amino acid
- cell therapy
- drug delivery
- nucleic acid
- cell death
- cancer therapy
- dna methylation
- mesenchymal stem cells
- oxidative stress
- drug induced
- binding protein
- nitric oxide
- endoplasmic reticulum stress
- free survival
- hyaluronic acid
- diabetic rats
- anti inflammatory