SPRTN metalloprotease participates in repair of ROS-mediated DNA-protein crosslinks.

Luke Erber, Arnold S Groehler, Cesar I Cyuzuzo, Jahan Baker-Wainwright, Reeja S Maskey, Lei Li, Yuichi J Machida, Natalia Tretyakova

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA. · pubmed

Paper

Abstract

Exposure to reactive oxygen species (ROS) can induce DNA-protein crosslinks (DPCs), unusually bulky DNA lesions that block replication and transcription and play a role in aging, cancer, cardiovascular disease, and neurodegenerative disorders. Repair of DPCs depends on the coordinated efforts of proteases and DNA repair enzymes to cleave the protein component of the lesion to smaller DNA-peptide crosslinks which can be processed by tyrosyl-DNA phosphodiesterases 1 and 2, nucleotide excision and homologous recombination repair pathways. DNA-dependent metalloprotease SPRTN plays a role in DPC repair, and SPRTN-deficient mice exhibit an accelerated aging phenotype and develop liver cancer early in life. We investigated the role of the SPRTN enzyme in the repair of DPCs produced by a free radical mechanism. Sprtn-deficient MEF cells treated with ionizing radiation had higher levels of total DPCs and exhibited greater sensitivity upon exposure to hydrogen peroxide and other crosslinking agents including cisplatin, phosphoramide mustard, and 1,2,3,4-diepoxybutane. Using a sensitive and accurate nanoLC-ESI

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Research summary

The paper investigates the role of the SPRTN metalloprotease in the repair of DNA-protein crosslinks induced by reactive oxygen species, which are implicated in aging and age-related diseases. By focusing on the mechanisms of DPC repair and the consequences of SPRTN deficiency, the research addresses a potential root cause of cellular aging and its associated pathologies. However, while the findings contribute to our understanding of DPC repair, the impact is somewhat limited as it primarily expands on existing knowledge rather than presenting a groundbreaking discovery.

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