Cadmium disrupts the DNA damage response by destabilizing RNF168

Food Chem Toxicol. 2019 Nov:133:110745. doi: 10.1016/j.fct.2019.110745. Epub 2019 Jul 31.

Abstract

Cadmium (Cd) is a dispensable element for the human body and is usually considered a carcinogen. Occupational and environmental Cd exposure leads to sustained cellular proliferation in some tissues and tumorigenesis via an unclear mechanism. Here, we evaluated the role of Cd in the DNA damage response (DDR). We found that Cd exposure causes extensive DNA double-strand breaks (DSBs) and prevents accumulation of ubiquitination signals at these sites of DNA damage. Cd treatment compromises 53BP1 and BRCA1 recruitment to DSBs induced by itself or DNA damaging agents and partially inactivates the G2/M checkpoint. Mechanistically, Cd directly binds to the E3 ubiquitin ligase RNF168, induces the ubiquitin-proteasome pathway that mediates RNF168 degradation and suppresses RNF168 ubiquitin-ligase activity in vitro. Our study raises the possibility that Cd may target RNF168 to disrupt proper DSB signaling in cultured cells. This pathway may represent a novel mechanism for carcinogenesis induced by Cd.

Keywords: Cadmium; DNA damage response; Double-stranded break; RNF168; Ubiquitination.

MeSH terms

  • BRCA1 Protein / metabolism
  • Cadmium / metabolism
  • Cadmium / toxicity*
  • Cadmium Compounds / toxicity*
  • Cell Line, Tumor
  • DNA / metabolism*
  • DNA Breaks, Double-Stranded / drug effects*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Histones / metabolism
  • Humans
  • Nitrates / toxicity*
  • Protein Binding
  • Tumor Suppressor p53-Binding Protein 1 / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / drug effects

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Cadmium Compounds
  • Histones
  • Nitrates
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Cadmium
  • DNA
  • RNF168 protein, human
  • Ubiquitin-Protein Ligases
  • cadmium nitrate