USP13 regulates the replication stress response by deubiquitinating TopBP1

DNA Repair (Amst). 2021 Apr:100:103063. doi: 10.1016/j.dnarep.2021.103063. Epub 2021 Feb 6.

Abstract

The DNA replication stress-induced checkpoint activated through the TopBP1-ATR axis is important for maintaining genomic stability. However, the regulation of TopBP1 in DNA-damage responses remains unclear. In this study, we identify the deubiquitinating enzyme (DUB) USP13 as an important regulator of TopBP1. Mechanistically, USP13 binds to TopBP1 and stabilizes TopBP1 by deubiquitination. Depletion of USP13 impedes ATR activation and hypersensitizes cells to replication stress-inducing agents. Furthermore, high USP13 expression enhances the replication stress response, promotes cancer cell chemoresistance, and is correlated with poor prognosis of cancer patients. Overall, these findings suggest that USP13 is a novel deubiquitinating enzyme for TopBP1 and coordinates the replication stress response.

Keywords: DNA damage; Replication; TopBP1; USP13.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Carrier Proteins / metabolism*
  • Cell Cycle Checkpoints*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • DNA / metabolism
  • DNA Damage*
  • DNA Replication*
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Nuclear Proteins / metabolism*
  • Ubiquitin-Specific Proteases / metabolism*
  • Ubiquitination*

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • TOPBP1 protein, human
  • DNA
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • USP13 protein, human
  • Ubiquitin-Specific Proteases