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

Scott J Pearson1, Tapasree Roy Sarkar1, Cole M McQueen1

  • 1Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.

Oncogene
|December 12, 2018
PubMed

Insights

SIM2s protein stabilizes DNA repair by enhancing homologous recombination (HR) and preventing cancer progression. Loss of SIM2s causes genomic instability and epithelial-mesenchymal transitions (EMT), promoting metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Genomic instability is crucial for cancer development.
  • DNA damage repair pathways are critical in maintaining genome stability.
  • Epithelial-mesenchymal transition (EMT) is a key process in cancer metastasis.

Purpose of the Study:

  • To investigate the role of SIM2s in DNA damage repair and cancer progression.
  • To elucidate the mechanism by which SIM2s regulates homologous recombination (HR) and EMT.
  • To establish a link between SIM2s, genomic instability, and metastasis.

Main Methods:

  • Investigated SIM2s interaction with ATM and BRCA1.
  • Analyzed ATM-dependent phosphorylation of SIM2s in response to ionizing radiation (IR).
  • Assessed HR efficiency and RAD51 recruitment upon SIM2s loss or mutation.
  • Evaluated EMT markers (E-cadherin, K14) and cancer cell invasion/metastasis.

Main Results:

  • SIM2s enhances HR-mediated DNA repair and prevents EMT in an ATM-dependent manner.
  • SIM2s interacts with ATM and is stabilized by ATM-dependent phosphorylation.
  • SIM2s collaborates with BRCA1 to facilitate RAD51 recruitment to DNA damage sites.
  • Loss or mutation of SIM2s impairs HR, leading to genomic instability and EMT induction.
  • SIM2s loss promotes invasion and metastasis by inducing EMT.

Conclusions:

  • SIM2s is a novel regulator of DNA damage repair and a suppressor of EMT.
  • SIM2s plays a critical role in preventing genomic instability and metastasis.
  • Loss of SIM2s links ductal carcinoma in situ to invasive ductal carcinoma progression.

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