ATM-dependent activation of SIM2s regulates homologous recombination and epithelial-mesenchymal transition

Oncogene. 2019 Apr;38(14):2611-2626. doi: 10.1038/s41388-018-0622-4. Epub 2018 Dec 10.

Abstract

There is increasing evidence that genomic instability is a prerequisite for cancer progression. Here we show that SIM2s, a member of the bHLH/PAS family of transcription factors, regulates DNA damage repair through enhancement of homologous recombination (HR), and prevents epithelial-mesenchymal transitions (EMT) in an Ataxia-telangiectasia mutated (ATM)-dependent manner. Mechanistically, we found that SIM2s interacts with ATM and is stabilized through ATM-dependent phosphorylation in response to IR. Once stabilized, SIM2s interacts with BRCA1 and supports RAD51 recruitment to the site of DNA damage. Loss of SIM2s through the introduction of shSIM2 or the mutation of SIM2s at one of the predicted ATM phosphorylation sites (S115) reduces HR efficiency through disruption of RAD51 recruitment, resulting in genomic instability and induction of EMT. The EMT induced by the mutation of S115 is characterized by a decrease in E-cadherin and an induction of the basal marker, K14, resulting in increased invasion and metastasis. Together, these results identify a novel player in the DNA damage repair pathway and provides a link in ductal carcinoma in situ progression to invasive ductal carcinoma through loss of SIM2s, increased genomic instability, EMT, and metastasis.

Publication types

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

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • BRCA1 Protein / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Cadherins / genetics
  • Carcinoma, Intraductal, Noninfiltrating / genetics
  • Cell Line, Tumor
  • DNA Damage / genetics
  • DNA Repair / genetics
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Genomic Instability / genetics
  • Homologous Recombination / genetics*
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Phosphorylation / genetics
  • Rad51 Recombinase / genetics

Substances

  • BRCA1 Protein
  • Basic Helix-Loop-Helix Transcription Factors
  • Cadherins
  • SIM2 protein, human
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Rad51 Recombinase