DNA protein crosslink proteolysis repair: From yeast to premature ageing and cancer in humans.

DNA Repair
John FieldenKristijan Ramadan


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.


Dec 29, 2018·Genes·Laura T LaranjoSusan T Lovett
Jan 19, 2019·Current Protocols in Nucleic Acid Chemistry·Pratibha P GhodkeF Peter Guengerich
Dec 10, 2019·FEMS Yeast Research·Ian W Dawes, Gabriel G Perrone
Jan 27, 2020·Environmental and Molecular Mutagenesis·Julie Rageul, Hyungjin Kim
Sep 29, 2019·Nature Reviews. Molecular Cell Biology·Hannes LansJurgen A Marteijn
Oct 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jang-Eun Cho, Sue Jinks-Robertson
Jan 11, 2020·Cell & Bioscience·Huimin ZhangJunjie Chen
Mar 11, 2020·Nature Communications·John FieldenKristijan Ramadan
Aug 28, 2020·Frontiers in Genetics·Ilya O VelegzhaninovDmitry Yu Klokov
Mar 14, 2020·Nature Communications·Yusuke KojimaYuichi J Machida
May 28, 2020·Cells·Alain DebecTimothy L Megraw
Nov 10, 2020·Nucleic Acids Research·Samuel HumeKristijan Ramadan
Jul 22, 2019·DNA Repair·Julie RageulHyungjin Kim
Dec 17, 2019·Developmental Cell·Gregoriy A DokshinMichelle A Carmell
Feb 11, 2021·The Journal of Biological Chemistry·Megan PerryGargi Ghosal
Jan 6, 2021·Communications Biology·Annamaria Ruggiano, Kristijan Ramadan
Feb 19, 2021·Critical Reviews in Toxicology·Chad M ThompsonHarvey J Clewell
Mar 7, 2021·International Journal of Molecular Sciences·Peter Polčic, Zdenko Machala
Mar 18, 2021·Autophagy·John FieldenKristijan Ramadan
Mar 21, 2021·Applied Microbiology and Biotechnology·Lahiru N Jayakody, Yong-Su Jin
Aug 31, 2021·The Journal of Biological Chemistry·Pratibha P Ghodke, F Peter Guengerich

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