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

Christelle Morris, Nozomi Tomimatsu, Derek J. Richard, David Cluet, Sandeep Burma, Kum Kum Khanna, Pierre Jalinot

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 G 2-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.

Original languageEnglish (US)
Pages (from-to)2006-2016
Number of pages11
JournalCancer Research
Volume72
Issue number8
DOIs
StatePublished - Apr 15 2012

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Ataxia Telangiectasia
DNA Damage
Zinostatin
Breast Neoplasms
Peptide Initiation Factors
Ubiquitination
RNA Interference
Cell Survival
Carcinogenesis
Phosphotransferases
Phosphorylation
Radiation
Gene Expression
DNA
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Morris, C., Tomimatsu, N., Richard, D. J., Cluet, D., Burma, S., Khanna, K. K., & Jalinot, P. (2012). INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells. Cancer Research, 72(8), 2006-2016. https://doi.org/10.1158/0008-5472.CAN-11-2562

INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells. / Morris, Christelle; Tomimatsu, Nozomi; Richard, Derek J.; Cluet, David; Burma, Sandeep; Khanna, Kum Kum; Jalinot, Pierre.

In: Cancer Research, Vol. 72, No. 8, 15.04.2012, p. 2006-2016.

Research output: Contribution to journalArticle

Morris, C, Tomimatsu, N, Richard, DJ, Cluet, D, Burma, S, Khanna, KK & Jalinot, P 2012, 'INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells', Cancer Research, vol. 72, no. 8, pp. 2006-2016. https://doi.org/10.1158/0008-5472.CAN-11-2562
Morris, Christelle ; Tomimatsu, Nozomi ; Richard, Derek J. ; Cluet, David ; Burma, Sandeep ; Khanna, Kum Kum ; Jalinot, Pierre. / INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells. In: Cancer Research. 2012 ; Vol. 72, No. 8. pp. 2006-2016.
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