TRAIP is a master regulator of DNA interstrand crosslink repair

• Published in: Nature (London) Vol. 567; no. 7747; pp. 267 - 272
• Main Authors: Wu, R. Alex, Semlow, Daniel R., Kamimae-Lanning, Ashley N., Kochenova, Olga V., Chistol, Gheorghe, Hodskinson, Michael R., Amunugama, Ravindra, Sparks, Justin L., Wang, Meng, Deng, Lin, Mimoso, Claudia A., Low, Emily, Patel, Ketan J., Walter, Johannes C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2019; Nature Publishing Group
• Subjects: 101/28; 13/106; 42/41; 631/337/1427; 631/45/147; 64/114; 82/1; 82/29; 82/83; Adenosine triphosphatase; Anemia; Animals; ATPases; Cancer treatment; Cdc45 protein; Chains; Chemotherapy; Crosslinking; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - biosynthesis; DNA - chemistry; DNA - metabolism; DNA helicase; DNA Helicases - chemistry; DNA Helicases - metabolism; DNA Repair; DNA Replication; Fanconi's anemia; Female; Genetic regulation; Genetic research; Genomes; Genomics; Homology; Humanities and Social Sciences; Humans; Letter; Ligases; Mammals; Minichromosome Maintenance Complex Component 7 - metabolism; multidisciplinary; Mutation; N-Glycosyl Hydrolases - metabolism; Protein Binding; Proteins; Repair; Replication; Replication forks; Resveratrol; Science; Science (multidisciplinary); Toxicity; Transcription; Transcription (Genetics); Ubiquitin; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Unloading; Xenopus
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1002-0

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 crosslink
1
; 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 recombination
2
. 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 findings
3
,
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.