DNA-protein cross-link repair: what do we know now?

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.

Keywords: DNA–protein cross-link; HR; NER; SPRTN; TDP1/TDP2.

Fig. 1

DPCs can be categorized as nonenzymatic or enzymatic based on the properties of the cross-linked proteins. Any proteins located in the vicinity of DNA can result in nonspecific DPCs triggered by various agents, including reactive compounds like aldehydes, metal ions, and several types of radiation. These are defined as nonenzymatic DPCs. Also, many DNA-related enzymatic reactions produce intermediates in which transient covalent linking between DNA and the enzyme occurs. Enzymes, such as DNA TOPs, DNA polymerases, and DNA methyltransferases, can be trapped and therefore form stable DPCs under certain circumstances. These are defined as enzymatic DPCs

Fig. 2

DPCs are composed of DNA, protein, and their cross-linked bonds, which can be targeted by different repair pathways. NER and HR are nuclease-dependent pathways that can directly cleave DNA molecules. The chemical bond between TOP1/TOP2 and DNA can be directly hydrolyzed by TDP1 and TDP2/ZNF451. Also, proteasomes, SPRTN/Wss1, and ACRC/GCNA-1 are related to proteolysis-dependent removal of covalently bound proteins