Mechanisms of DNA-protein cross-link formation and repair

Covalent binding of DNA to proteins produces DNA-protein cross-links (DPCs). DPCs are formed as intermediates of enzymatic processes, generated from the reactions of protein nucleophiles with DNA electrophiles, and produced by endogenous and exogenous cross-linking agents. DPCs are heterogeneous due to the variations of DNA conjugation sites, flanking DNA structures, protein sizes, and cross-link bonds. Unrepaired DPCs are toxic because their bulky sizes physically block DNA replication and transcription, resulting in impaired genomic integrity. Compared to other types of DNA lesions, DPC repair is less understood. Emerging evidence suggests a general repair model that DPCs are proteolyzed by the proteasome and/or DPC proteases, followed by the peptide removal through canonical repair pathways. Herein, we first describe the recently discovered DPCs. We then review the mechanisms of DPC proteolysis with the focus on recently identified DPC proteases. Finally, distinct pathways that bypass or remove the cross-linked peptides following proteolysis are discussed.