TRAIP is a master regulator of DNA interstrand crosslink repair

R. Alex Wu, Daniel R. Semlow, Ashley N. Kamimae-Lanning, Olga V. Kochenova, Gheorghe Chistol, Michael R. Hodskinson, Ravindra Amunugama, Justin L. Sparks, Meng Wang, Lin Deng, Claudia A. Mimoso, Emily Low, Ketan J. Patel and Johannes C. Walter ()
Additional contact information
R. Alex Wu: Harvard Medical School
Daniel R. Semlow: Harvard Medical School
Ashley N. Kamimae-Lanning: Cambridge Biomedical Campus
Olga V. Kochenova: Harvard Medical School
Gheorghe Chistol: Harvard Medical School
Michael R. Hodskinson: Cambridge Biomedical Campus
Ravindra Amunugama: Harvard Medical School
Justin L. Sparks: Harvard Medical School
Meng Wang: Cambridge Biomedical Campus
Lin Deng: Harvard Medical School
Claudia A. Mimoso: Harvard Medical School
Emily Low: Harvard Medical School
Ketan J. Patel: Cambridge Biomedical Campus
Johannes C. Walter: Harvard Medical School

Nature, 2019, vol. 567, issue 7747, 267-272

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1002-0

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