TRAIP is a master regulator of DNA interstrand cross-link repair
By R. A. Wu, Daniel R. Semlow, Ashley N. Kamimae-Lanning, O. V. Kochenova, Gheorghe Chistol, M. Hodskinson, R. Amunugama, Justin L. Sparks, Meng Wang, Lin Deng and 4 more. 2019
169 citations recorded by the source corpus.
Cells often use multiple pathways to repair the same DNA lesion, and the choice of pathway has substantial implications for the fidelity of genome maintenance. DNA interstrand crosslinks covalently link the two strands of DNA, and thereby block replication and transcription; the cytotoxicity of these crosslinks is exploited for chemotherapy. In Xenopus egg extracts, the collision of replication forks with interstrand crosslinks initiates two distinct repair pathways. NEIL3 glycosylase can cleave the crosslink1; however, if this fails, Fanconi anaemia proteins incise the phosphodiester backbone that surrounds the interstrand crosslink, generating a double-strand-break intermediate that is repaired by homologous recombination2. It is not known how the simpler NEIL3 pathway is prioritized over the Fanconi anaemia pathway, which can cause genomic rearrangements. Here we show that the E3 ubiquitin ligase TRAIP is required for both pathways. When two replisomes converge at an interstrand crosslink, TRAIP ubiquitylates the replicative DNA helicase CMG (the complex of CDC45, MCM2–7 and GINS). Short ubiquitin chains recruit NEIL3 through direct binding, whereas longer chains are required for the unloading of CMG by the p97 ATPase, which enables the Fanconi anaemia pathway. Thus, TRAIP controls the choice between the two known pathways of replication-coupled interstrand-crosslink repair. These results, together with our other recent findings3,4 establish TRAIP as a master regulator of CMG unloading and the response of the replisome to obstacles. The E3 ubiquitin ligase TRAIP governs the choice between the NEIL3 or the Fanconi anaemia pathway for the repair of DNA interstrand crosslinks.
Subfields: Cell Biology, Molecular Biology
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Citations in the corpus
- In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, methodology): “Rabbit polyclonal antibodies against the following proteins were used as primary antibodies for Western blotting: DONSON (1:5000, described above) MCM7 [1:12,000, (31)] MCM4 (1:4000, Bethyl #A300-193A, RRID: AB_162720) MCM3 (1:4000, SantaCruz (H-215) #sc-292857) CDC45 [1:20,000, (56)] GINS [1:5000, ”