DNA-Protein Crosslink Repair Mechanisms

DNA-protein crosslinks (DPCs) are bulky lesions formed when proteins become covalently attached to DNA, arising from endogenous metabolism, environmental agents or the action of specialised enzymes such as topoisomerases. These adducts impede both replication and transcription, threatening genome stability and cellular viability. Cells deploy multiple, often overlapping pathways to resolve DPCs. During S phase, replication-coupled proteolysis by the DNA-dependent metalloprotease SPRTN and the proteasome dismantles the crosslinked protein, aided by ubiquitin ligase activities and accessory factors such as the p97/VCP ATPase. In parallel, certain helicases, notably FANCJ, unfold protein adducts to facilitate protease access and translesion synthesis. If peptides persist, homologous recombination can rescue stalled forks. Beyond replication, transcription-coupled DPC repair engages stalled RNA polymerase II, Cockayne syndrome proteins, the proteasome and VCP to clear lesions in active genes. Additional layers of regulation involve SUMO and NEDD8 modifications, selective autophagy of trapped topoisomerase complexes and endonucleolytic incision by structure-specific nucleases. Together, these mechanisms protect against ageing, neurodegeneration and cancer and underpin therapeutic strategies that exploit DPC repair deficiencies.

Research from Nature Portfolio

Insights into replication-coupled ubiquitin-proteasome repair have been deepened by studies showing that inhibition of NEDD8 conjugation sensitises colorectal cancer cells to topoisomerase I inhibitors. This work revealed that a CRL4 ubiquitin ligase complex, with DCAF13 as a receptor, tags trapped TOP1 cleavage complexes for proteasomal degradation in a replication-dependent manner, establishing a mechanistic and translational rationale for drug combinations in oncology. In parallel, high-resolution mapping of aldehyde-induced DPCs has defined a transcription-coupled repair pathway: stalled RNA polymerase II recruits the canonical TCR machinery together with VCP and the 26S proteasome, while TFIIS-mediated transcript cleavage promotes lesion bypass. Mouse models deficient in both aldehyde clearance and TCR confirm that failure to remove endogenous DPCs in active genes underlies progeroid and Cockayne syndrome-like phenotypes.

DNA-Protein Crosslink Repair Mechanisms publication trend

The graph below shows the total number of articles in dna-protein crosslink repair mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

DNA-protein crosslink (DPC): A covalent bond between a protein and DNA that obstructs replication and transcription.

Replication-coupled proteolysis: The process by which proteases such as SPRTN and the proteasome degrade proteins crosslinked to DNA during S phase.

Transcription-coupled repair (TCR): A specialised pathway that removes lesions blocking RNA polymerase II in actively transcribed genes.

Ubiquitination: The covalent attachment of ubiquitin to a protein, often signalling it for degradation by the proteasome.

SUMOylation: The conjugation of a small ubiquitin-like modifier (SUMO) to target proteins, regulating DPC recognition and repair.

NEDDylation: The attachment of the ubiquitin-like protein NEDD8 to cullin ligases, modulating ubiquitin-mediated DPC repair.

p97/VCP ATPase: A molecular motor that extracts ubiquitinated proteins from chromatin, facilitating access for proteases and repair factors.

References

1. TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival. Cell (2024).
2. Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex. Nature Communications (2023).
3. Endogenous aldehyde-induced DNA–protein crosslinks are resolved by transcription-coupled repair. Nature Cell Biology (2024).
4. The FANCJ helicase unfolds DNA-protein crosslinks to promote their repair. Molecular Cell (2023).
5. Transcription-coupled repair of DNA–protein crosslinks. Trends in Cell Biology (2024).
6. Replication-Coupled DNA-Protein Crosslink Repair by SPRTN and the Proteasome in Xenopus Egg Extracts. Molecular Cell (2018).