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Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice

Oncogene volume 29, pages 2877–2883 (2010)Cite this article

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Abstract

Poly(ADP-ribose) polymerase-2 (Parp-2) belongs to a family of enzymes that catalyse poly(ADP-ribosyl)ation of proteins. Parp-2 deficiency in mice (Parp-2−/−) results in reduced thymic cellularity associated with increased apoptosis in thymocytes, defining Parp-2 as an important mediator of T-cell survival during thymopoiesis. To determine whether there is a link between Parp-2 and the p53 DNA-damage-dependent apoptotic response, we have generated Parp-2/p53-double-null mutant mice. We found that p53−/− backgrounds completely restored the survival and development of Parp-2−/− thymocytes. However, Parp-2-deficient thymocytes accumulated high levels of DNA double-strand breaks (DSB), independently of the p53 status, in line with a function of Parp-2 as a caretaker promoting genomic stability during thymocytes development. Although Parp-2−/− mice do not have spontaneous tumours, Parp-2 deficiency accelerated spontaneous tumour development in p53-null mice, mainly T-cell lymphomas. These data suggest a synergistic interaction between Parp-2 and p53 in tumour suppression through the role of Parp-2 in DNA-damage response and genome integrity surveillance, and point to the potential importance of examining human tumours for the status of both genes.

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Acknowledgements

We thank Katherine Papageorgiou for assistance with handling the mice and Sergi Mojal for statistical analysis support. This work was supported by Spanish Ministerio de Ciencia e Innovación (Grant SAF2008-01572 to JY); Generalitat de Catalunya (Grant 2009/SGR/524 to JY); Instituto de Salud Carlos III (Grant PI081150 to PA); Fundación Séneca (Grant 08643/PI/08 to PA); and funds from Centre National de la Recherche Scientifique, Association pour la Recherche contre le Cancer, Electricité de France, Comité du Haut-Rhin de la Ligue Nationale Contre le Cancer and Commissariat à l’Energie Atomique (VS, FD). LN is supported by the Spanish Ministerio de Ciencia e Innovación and AB-M is supported by Instituto de Salud Carlos III (Madrid, Spain) and the FFIS (Murcia, Spain).

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Authors and Affiliations

  1. Department of Immunology, IMIM-Hospital del Mar, Barcelona Biomedical Research Park, Barcelona, Spain

    L Nicolás, C Ampurdanés, J Martin-Caballero & J Yelamos

  2. Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Murcia, Murcia, Spain

    L Nicolás & P Aparicio

  3. Department of Surgery, CIBERehd, University Hospital ‘Virgen de la Arrixaca’, University of Murcia, Murcia, Spain

    C Martínez & A Baroja-Mazo

  4. Department of Pathology, IMIM-Hospital del Mar, Barcelona Biomedical Research Park, Barcelona, Spain

    C Baró, M Rodríguez & F Sole

  5. Department of Animal Surgery and Medicine, School of Veterinary, University Complutense of Madrid, Madrid, Spain

    J M Flores

  6. IREBS-FRE3211, ESBS, bld Sébastien Brant, Strasbourg, France

    F Dantzer

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  1. L Nicolás
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Correspondence to J Yelamos.

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Nicolás, L., Martínez, C., Baró, C. et al. Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice. Oncogene 29, 2877–2883 (2010). https://doi.org/10.1038/onc.2010.11

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