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 (2012) INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells. Cancer Research, 72(8), pp. 2006-2016.

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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 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.

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ID Code: 55941
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Keywords: INT6/EIF3E , ATM, DNA Damage Response
DOI: 10.1158/0008-5472.CAN-11-2562
ISSN: 1538-7445
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Genetics (111203)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 American Association for Cancer Research
Deposited On: 21 Dec 2012 01:21
Last Modified: 28 Jan 2015 00:43

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