Abstract
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.
Highlights
single-stranded/double-stranded DNA (DNA)-protein crosslinks (DPCs) are frequent and toxic DNA lesions, as they impede essential DNA transactions
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
Aldehydes are released during lipid peroxidation, histone demethylation and alcohol breakdown, implying that threats posed by DPCs are ubiquitous [2,3]; aldehydes are present in the environment
Summary
DNA-protein crosslinks (DPCs) are frequent and toxic DNA lesions, as they impede essential DNA transactions. The chromatin environment is generally crowded and exposed to a variety of crosslinking agents, meaning any protein in the vicinity of DNA can potentially be crosslinked to DNA. Considering their bulky nature, DPCs present major barriers, especially to DNA replication and transcription [1], causing DNA replication stress and genomic instability; DPC removal is essential for cell survival [8]. The effort of several laboratories has brought a new pathway to the attention of the DNA repair field This repair mechanism is specific for DPCs and is carried out by replication-coupled DNA-dependent proteases in eukaryotes. We will present Top-cc as a prototypical DPC with significant medical implications and discuss how DPC formation is exploited in cancer therapy
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