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Cited by 21DNA Repair MechanismsEffects of Radiation ExposureCancer-related Molecular Pathways

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INT6/EIF3E Interacts with ATM and Is Required for Proper Execution of the DNA Damage Response in Human Cells

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Morris, Christelle, Tomimatsu, Nozomi, Richard, Derek J., Cluet, David, Burma, Sandeep, Khanna, Kum Kum, Jalinot, Pierre·2012·Cancer Research
DOI 10.1158/0008-5472.can-11-2562PMC PMC3335344

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Abstract

Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following γ-irradiation and G2–M checkpoint control. RNA interference–mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with γ-radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response. Cancer Res; 72(8); 2006–16. ©2012 AACR.

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Metadata

Authors
Morris, C., Tomimatsu, N., Richard, D. J., Cluet, D., Burma, S., Khanna, K. K., & Jalinot, P.
Affiliations
École Normale Supérieure de Lyon (FR)
Corresponding author
Jalinot, Pierre
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2012-04-15
Volume
72
Issue
8
Pages
2006-2016
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-11-2562
PMC
PMC3335344
OpenAlex
W1607050441
Cited by
21
References
3
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 4
FWCI
0.64
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion)
  • HAL (submittedVersion)
Funders
National Cancer Institute (R01CA149461)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
INT6, eIF3e, ATM, DNA damage response, Chk1, Chk2, G2/M checkpoint, gamma irradiation, neocarzinostatin, BRCA1, ubiquitination, DNA repair, breast cancer, protein-protein interaction
MeSH terms
Cell Survival, Cell Transformation, Neoplastic, DNA Damage, DNA-Binding Proteins, Fluorescent Antibody Technique, Humans, Immunoblotting, Protein Serine-Threonine Kinases, Microscopy, Confocal, Cell Cycle Proteins, BRCA1 Protein, Tumor Suppressor Proteins, Eukaryotic Initiation Factor-3, Cell Line, Tumor, Immunoprecipitation, Gene Knockdown Techniques, Cell Cycle Checkpoints, Ataxia Telangiectasia Mutated Proteins

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