Abstract
When a protein is covalently and irreversibly bound to DNA (i.e., a DNA-protein cross-link [DPC]), it may obstruct any DNA-based transaction, such as transcription and replication. DPC formation is very common in cells, as it can arise from endogenous factors, such as aldehyde produced during cell metabolism, or exogenous sources like ionizing radiation, ultraviolet light, and chemotherapeutic agents. DPCs are composed of DNA, protein, and their cross-linked bonds, each of which can be targeted by different repair pathways. Many studies have demonstrated that nucleotide excision repair and homologous recombination can act on DNA molecules and execute nuclease-dependent DPC repair. Enzymes that have evolved to deal specifically with DPC, such as tyrosyl-DNA phosphodiesterases 1 and 2, can directly reverse cross-linked bonds and release DPC from DNA. The newly identified proteolysis pathway, which employs the proteases Wss1 and SprT-like domain at the N-terminus (SPRTN), can directly hydrolyze the proteins in DPCs, thus offering a new venue for DPC repair in cells. A deep understanding of the mechanisms of each pathway and the interplay among them may provide new guidance for targeting DPC repair as a therapeutic strategy for cancer. Here, we summarize the progress in DPC repair field and describe how cells may employ these different repair pathways for efficient repair of DPCs.