biostudies-literatureUnknownKochenova OVEuropean Research CouncilNHLBI NIH HHSThe E3 ubiquitin ligase TRAIP associates with the replisome and helps this molecular machine deal with replication stress. Thus, TRAIP promotes DNA inter-strand crosslink repair by triggering the disassembly of CDC45-MCM2-7-GINS (CMG) helicases that have converged on these lesions. However, disassembly of single CMGs that have stalled temporarily would be deleterious, suggesting that TRAIP must be carefully regulated. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. We further show that TRAIP loss rescues the hypersensitivity of <i>USP37</i> knockout cells to topoisomerase inhibitors. In <i>Xenopus</i> egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitbioRxiv : the preprint server for biology2024.09.03.611025https://www.ebi.ac.uk/biostudies/studies/S-EPMC11398331biostudies-literatureUSP37 prevents premature disassembly of stressed replisomes by TRAIP.PMC11398331R01 HL098316855741Jhujh SSVoigt AGupta VGueorguieva NSchmid EJackson SPStewart GSWu RAWalter JCRichards SLGarcia MRPilger DD'Alessandro GKochenova OVCarnie CJfalseUSP37 prevents premature disassembly of stressed replisomes by TRAIP.The E3 ubiquitin ligase TRAIP associates with the replisome and helps this molecular machine deal with replication stress. Thus, TRAIP promotes DNA inter-strand crosslink repair by triggering the disassembly of CDC45-MCM2-7-GINS (CMG) helicases that have converged on these lesions. However, disassembly of single CMGs that have stalled temporarily would be deleterious, suggesting that TRAIP must be carefully regulated. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. We further show that TRAIP loss rescues the hypersensitivity of <i>USP37</i> knockout cells to topoisomerase inhibitors. In <i>Xenopus</i> egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquit2024-01-01T00:00:00Z2024 Sep2026-04-21T03:22:08.07Z2025-04-04T02:45:43.769ZS-EPMC113983313928231410.1101/2024.09.03.611025