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INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells

Christelle Morris1, Nozomi Tomimatsu, Derek J Richard

  • 1Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Lyon, France.

Cancer Research
|April 18, 2012
PubMed

Insights

The INT6 gene is crucial for DNA damage response and cell survival, protecting against breast cancer by aiding DNA repair mechanisms involving ATM and BRCA1.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • DNA Damage Response

Background:

  • Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, is observed in human breast cancers.
  • The precise role of INT6 in carcinogenesis and its relationship with DNA damage response pathways remain unestablished.

Purpose of the Study:

  • To investigate the involvement of INT6 in the DNA damage response.
  • To elucidate the molecular mechanisms linking INT6 to DNA repair and breast cancer onset.

Main Methods:

  • Utilized RNA interference (RNAi) to silence INT6 expression.
  • Assessed cell survival and G(2)-M checkpoint control following gamma-irradiation.
  • Measured phosphorylation of checkpoint kinases (CHK1, CHK2) and accumulation of ATM and BRCA1 at DNA damage sites.

Main Results:

  • INT6 is essential for cell survival and G(2)-M checkpoint control after DNA damage.
  • INT6 silencing impaired CHK1/CHK2 phosphorylation and prevented ATM accumulation at damage sites.
  • INT6 interacts with ATM, and its absence disrupts ubiquitylation and BRCA1 accumulation at DNA lesions.

Conclusions:

  • INT6 plays a critical role in the DNA damage response through its interaction with ATM and involvement in DNA repair processes.
  • INT6's protective effect against breast cancer onset is linked to its function in maintaining genomic integrity via DNA repair pathways.
  • Findings reveal novel connections between INT6, ATM, and BRCA1 in DNA damage response and cancer prevention.

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