Journal article
Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair
B Vaz, M Popovic, JA Newman, J Fielden, H Aitkenhead, S Halder, AN Singh, I Vendrell, R Fischer, I Torrecilla, N Drobnitzky, R Freire, DJ Amor, PJ Lockhart, BM Kessler, GW McKenna, O Gileadi, K Ramadan
Molecular Cell | CELL PRESS | Published : 2016
Abstract
The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication..
View full abstractGrants
Awarded by European Commission
Funding Acknowledgements
This work was supported by the Medical Research Council programme grant (MC_PC_12001/1) to K.R., the Goodger Scholarship of the University of Oxford to S.H., the John Fell Fund 133/075 and the Wellcome Trust grant 097813/Z/11/Z to B.M.K, the Kennedy Trust Fund to R.F. and B.M.K, and the NHMRC Career Development Fellowship (GNT1032364) to P.L. This work was also supported by Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. O.G., J.A.N., and H.A. are funded by the SGC, a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust (106169/ZZ14/Z).