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The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-γ-mediated apoptosis

Oncogene volume 24, pages 5492–5501 (2005)Cite this article

Abstract

BRCA1 has been reported to have roles in DNA damage repair, cell cycle checkpoint control, transcriptional regulation and ubiquitination. We have previously demonstrated that BRCA1 is a potent activator of a subset of interferon (IFN)-regulated genes and that BRCA1 synergistically activated a number of these genes in the presence of IFN-γ, but not type I IFNs. Here we report that one of these targets, 2,5 oligoadenylate synthetase (2,5 OAS), is a mediator of BRCA1/IFN-γ-induced apoptosis. We show that the induction of 2,5 OAS in response to IFN-γ is BRCA1 and STAT1 dependent. Consistent with a role as a negative regulator of proliferation, transient transfection of 2,5 OAS into breast cancer cell lines results in decreased colony growth and apoptosis. Furthermore we show that IFN-γ-induced apoptosis is dependent on functional BRCA1 and STAT1 and we demonstrate that IFN-γ-induced apoptosis is dependent on 2,5 OAS induction. 2,5 OAS is the only known upstream regulator of RNaseL, a recently identified hereditary prostate tumour suppressor gene implicated in apoptosis. We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-γ to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis.

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Acknowledgements

This work was funded by grants from Cancer Research UK, Action Cancer, and the Research and Development Office, Northern Ireland.

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Author notes

  1. Paul B Mullan and Alison M Hosey: These authors contributed equally to this work

Authors and Affiliations

  1. Centre for Cancer Research and Cell Biology, Queen's University Belfast, University Floor, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, UK

    Paul B Mullan, Alison M Hosey, Niamh E Buckley, Jennifer E Quinn, Richard D Kennedy, Patrick G Johnston & D Paul Harkin

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  1. Paul B Mullan
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  2. Alison M Hosey
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  4. Jennifer E Quinn
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  7. D Paul Harkin
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Correspondence to D Paul Harkin.

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Mullan, P., Hosey, A., Buckley, N. et al. The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-γ-mediated apoptosis. Oncogene 24, 5492–5501 (2005). https://doi.org/10.1038/sj.onc.1208698

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