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Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications
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Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications

Published on: April 21, 2023

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Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

Bruno Vaz1, Marta Popovic1, Joseph A Newman2

  • 1Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.

Molecular Cell
|November 23, 2016
PubMed

Insights

SPRTN protease repairs DNA-protein crosslinks (DPCs) that block DNA replication. This discovery reveals a new pathway essential for genome stability and understanding diseases like Ruijs-Aalfs syndrome.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA-protein crosslinks (DPCs) are cytotoxic lesions that impede DNA replication.
  • Cellular mechanisms for repairing DPCs are not fully elucidated.
  • DPCs arise from endogenous metabolic processes and exogenous agents.

Purpose of the Study:

  • To identify and characterize novel factors involved in DNA-protein crosslink repair.
  • To elucidate the role of SPRTN protease in maintaining genome stability during DNA replication.
  • To understand the molecular basis of Ruijs-Aalfs syndrome (RJALS).

Main Methods:

  • Biochemical assays to assess protease activity.
  • Cell-based studies using patient-derived cells with SPRTN mutations.
  • Analysis of DNA replication fork progression and DPC clearance.

Main Results:

  • SPRTN is identified as a DNA-dependent metalloprotease that cleaves DNA-binding substrates.
  • SPRTN functions in a DNA replication-coupled manner to remove DPCs.
  • SPRTN deficiency in RJALS cells leads to replication fork stalling and hypersensitivity to DPC-inducing agents.

Conclusions:

  • SPRTN protease mediates a specialized DNA replication-coupled pathway for DPC repair.
  • Defects in SPRTN-dependent DPC clearance underlie RJALS pathogenesis.
  • SPRTN is crucial for protecting proliferative cells from DPC toxicity, impacting genome stability, aging, and cancer risk.
Keywords:
DNA replicationDNA-dependent metalloproteaseDNA-protein crosslink repairRuijs-Aalfs/SPARTAN syndromeSPARTAN/DVC1agingcancer

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