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.
Journal article
Mol Cell
17/11/2016
64
704 - 719
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