Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.

Original publication

DOI

10.1016/j.molcel.2016.09.032

Type

Journal article

Journal

Mol Cell

Publication Date

17/11/2016

Volume

64

Pages

704 - 719

Keywords

DNA replication, DNA-dependent metalloprotease, DNA-protein crosslink repair, Ruijs-Aalfs/SPARTAN syndrome, SPARTAN/DVC1, aging, cancer, Amino Acid Sequence, Binding Sites, Cross-Linking Reagents, DNA, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, Etoposide, Formaldehyde, Gene Expression, Genomic Instability, Humans, Kinetics, Mutation, Protein Binding, Sequence Alignment, Sequence Homology, Amino Acid, Substrate Specificity, Syndrome, Ultraviolet Rays