Aitkenhead, H; Amor, DJ; Drobnitzky, N; Fielden, J; Fischer, R; Freire, R; Gileadi, O; Halder, S; Kessler, BM; Lockhart, PJ; Mckenna, GW; Newman, JA; Popovic, M; Ramadan, K; Singh, AN; Torrecilla, I; Vaz, B; Vendrell, I
704-719. [Molecular cell]
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.
Amino Acid Sequence; Binding Sites; Cross-Linking Reagents/chemistry; DNA/chemistry/genetics/metabolism; DNA Damage; DNA Repair; DNA Replication; DNA-Binding Proteins/genetics/metabolism; Etoposide/chemistry; Formaldehyde/chemistry; Gene Expression; Genomic Instability; Kinetics; Mutation; Protein Binding; Sequence Alignment; Sequence Homology, Amino Acid; Substrate Specificity; Syndrome; Ultraviolet Rays; DNA replication; DNA-dependent metalloprotease; DNA-protein crosslink repair; Ruijs-Aalfs/SPARTAN syndrome; SPARTAN/DVC1; cancer; 1HG84L3525; 6PLQ3CP4P3; 9007-49-2