In general, there are multiple pathways taken by cells to repair the same DNA damage, and the choice of repair pathway is important for maintaining genomic fidelity. Cross-linking between DNA strands covalently links two DNA strands together, thereby blocking DNA replication and transcription, chemotherapy takes effect by utilizing the cytotoxicity of these crosslinks. In Xenopus laevis egg extracts, the collision of the replication fork with the interstrand crosslinker initiated two different repair pathways.
NEIL3 glycosylase is capable of cleaving cross-linkages between DNA strands; however, if this cleavage is not successful, the Fanconi anaemia protein will cleave the phosphodiester backbone surrounding the cross-linker of the DNA strand, producing a double-strand break intermediate that is subsequently repaired by homologous recombination. Prior to this, it was not clear how the relatively simple NEIL3 pathway would take precedence over the Fanconi anemia pathway that led to genomic rearrangement. In a new study, Johannes C. Walter of Harvard Medical School and his team found that both pathways require the E3 ubiquitin ligase TRAIP, related research results were published in the journal of Nature.
When two copies (replisome, protein complexes involved in DNA replication) converge on DNA strand crosslinks, TRAIP allows DNA replication helicase CMG ubiquitination (complex composed of CDC45, MCM2–7 and GINS). The shorter ubiquitin chains recruit NEIL3 by direct binding, whereas the longer ubiquitin chain is required for the p97 ATPase to unload CMG, which makes the Fanconi anemia pathway become possible. Therefore, in the repair of interstrand crosslinks associated with DNA replication, TRAIP controls the choice of these two repair pathways.
In summary, these findings, together with other recent findings from the Walter team, established that TRAIP is the primary regulator of CMG unloading and replicating responses to interstrand crosslinks.
R. Alex Wu et al. TRAIP is a master regulator of DNA interstrand crosslink repair. Nature, 2019, doi:10.1038/s41586-019-1002-0.