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DNA protein crosslink proteolysis repair: From yeast to premature ageingand cancer in humans

Fielden, John; Ruggianoa, Annamaria; Popović, Marta; Ramadan, Kristijan (2018) DNA protein crosslink proteolysis repair: From yeast to premature ageingand cancer in humans. DNA Repair, 71 . pp. 198-204. ISSN 1568-7864 (In Press)

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DNA-protein crosslinks (DPCs) are a specific type of DNA lesion consisting of a protein covalently and irreversibly bound to DNA, which arise after exposure to physical and chemical crosslinking agents. DPCs can be bulky and thereby pose a barrier to DNA replication and transcription. The persistence of DPCs during S phase causes DNA replication stress and genome instability. The toxicity of DPCs is exploited in cancer therapy: many common chemotherapeutics kill cancer cells by inducing DPC formation. Recent work from several laboratories discovered a specialized repair pathway for DPCs, namely DPC proteolysis (DPCP) repair. DPCP repair is carried out by replication-coupled DNA-dependent metalloproteases: Wss1 in yeast and SPRTN in metazoans. Mutations in SPRTN cause premature ageing and liver cancer in humans and mice ; thus, defective DPC repair has great clinical ramifications. In the present review, we will revise the current knowledge on the mechanisms of DPCP repair and on the regulation of DPC protease activity, while highlighting the most significant unresolved questions in the field. Finally, we will discuss the impact of faulty DPC repair on disease and cancer therapy.

Item Type: Article
Uncontrolled Keywords: DNA-protein crosslinks; SPRTN protease; post-translational modification; genome stability; ageing; cancer
Subjects: NATURAL SCIENCES > Biology
NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions: Division for Marine and Enviromental Research
Depositing User: Marta Popović
Date Deposited: 07 Nov 2018 14:55
DOI: 10.1016/j.dnarep.2018.08.025

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