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Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage

Oncogene volume 26, pages 6167–6175 (2007)Cite this article

Abstract

H4(D10S170) gene has been identified upon its frequent rearrangement with RET in papillary thyroid tumours (RET/PTC1). The kinase ataxia telangectasia mutated (ATM) phosphorylates a limited number of downstream protein targets in response to DNA damage. We investigated the potential role of H4(D10S170) in DNA damage signaling pathways. We found that in cells treated with etoposide or ionizing radiation (IR), H4(D10S170) underwent ATM-mediated phosphorylation at Thr 434, stabilizing nuclear H4. In ataxia telangectasia cells (A-T), endogenous H4(D10S170) was localized to cytoplasm and was excluded from the nucleus. Moreover, H4(D10S170) was not phosphorylated in ATM-deficient lymphoblasts after ionizing irradiation. Inhibition of ATM kinase interfered with H4(D10S170) apoptotic activity, and expression of H4 with threonine 434 mutated in Alanine, H4T434A, protected the cells from genotoxic stress-induced apoptosis. Most importantly, after exposure to IR we found that silencing of H4(D10S170) in mammalian cells increased cell survival, as shown by clonogenic assay, allows for DNA synthesis as evaluated by bromodeoxyuridine incorporation and permits cells to progress into mitosis as demonstrated by phosphorylation on Histone H3. Our results suggest that H4(D10S170) is involved in cellular response to DNA damage ATM-mediated, and that the impairment of H4(D10S170) gene function might have a role in thyroid carcinogenesis.

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Acknowledgements

We are grateful to Massimo Santoro for helpful discussion and encouragements. We are indebted to Tommaso Russo for critical remarks and suggestions. This study was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC).

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Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare, University ‘Federico II’, Naples, Italy

    F Merolla, F Pentimalli, G Vecchio & A Fusco

  2. CNR Istituto di Biostrutture e Bioimmagini, Naples, Italy

    R Pacelli

  3. Dipartimento di Medicina Sperimentale e Clinica, Università ‘Magna Graecia’, Catanzaro, Italy

    M Grieco

  4. Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy

    A Celetti

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  1. F Merolla
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  2. F Pentimalli
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  3. R Pacelli
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  4. G Vecchio
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  5. A Fusco
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  6. M Grieco
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  7. A Celetti
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Correspondence to A Celetti.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Merolla, F., Pentimalli, F., Pacelli, R. et al. Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage. Oncogene 26, 6167–6175 (2007). https://doi.org/10.1038/sj.onc.1210446

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