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Nature January 1, 2019; 567 (7747): 267-272.
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TRAIP is a master regulator of DNA interstrand crosslink repair.

Wu RA , Semlow DR , Kamimae-Lanning AN , Kochenova OV , Chistol G , Hodskinson MR , Amunugama R , Sparks JL , Wang M , Deng L , Mimoso CA , Low E , Patel KJ , Walter JC .

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.

PubMed ID: 30842657
PMC ID: PMC6417926
Article link: Nature
Grant support: [+]

Species referenced: Xenopus
Genes referenced: atr bard1 brca1 cdc45 cdc7 cdk1 chek1 cul2 eif4g2 fancd2 fancl fancm ghrh gmnn hap1 kidins220 lrr1 mcm2 mcm4 mcm6.2 mcm7 neil3 phf20 usp2

Article Images: [+] show captions
References [+] :
Amunugama, Replication Fork Reversal during DNA Interstrand Crosslink Repair Requires CMG Unloading. 2019, Pubmed, Xenbase