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Human Molecular Genetics Advance Access published online on September 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi324
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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received June 22, 2005
Revised August 11, 2005
Accepted August 19, 2005

Article

Impaired genomic stability and increased oxidative stress exacerbate different features of A-T

Shelly Ziv 1, Ori Brenner 2, Ninette Amariglio 3, Nechama I. Smorodinsky 4, Ronit Galron 1, Danaise V Carrion 5, Weijia Zhang 5, Girdhar G. Sharma 6, Raj K. Pandita 6, Manjula Agarwal 6, Ran Elkon 7, Nirit Katzin 8, Irit Bar-Am 8, Tej K. Pandita 6, Raju Kucherlapati 5, Gideon Rechavi 3, Yosef Shiloh 7, and Ari Barzilai 1*

1 Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
2 Department of Veterinary Resources, the Weizmann Institute of Science, Rehovot 76100, Israel,
3 Department of Pediatric Hematology-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52126, and Sackler School of Medicine, Tel Aviv University, Israel
4 Alec and Myra Marmot Hybridoma Laboratory, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
5 Departments of Medicine and Genetics and Harvard Partners Center for Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA
6 Department of Oncology and Radiation, Washington University, School of Medicine, St. Louis, MO 63108, USA
7 Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
8 Applied Spectral Imaging, Migdal Haemek 10551, Israel

* To whom correspondence should be addressed.
Ari Barzilai, E-mail: barzilai{at}post.tau.ac.il


  Abstract

Ataxia-telangiectasia (A-T) is a multisystem, cancer-predisposing genetic disorder caused by deficiency of the ATM protein. In order to dissect the A-T phenotype, we augmented specific features of the human disease by generating mouse strains that combine Atm deficiency with dysfunction of other proteins. Increasing oxidative stress by combining deficiencies in Atm and superoxide dismutase 1 (Sod1) exacerbated growth retardation and markedly reduced the mean survival time following ionizing radiation (IR). On the other hand, increasing genomic instability by combining deficiencies of Atm and the mismatch repair protein Mlh1 caused a moderate increase in radiation sensitivity and dramatic increase in aggressive lymphomas, compared to the Atm-/- single knockout. Remarkably, Atm, Mlh1 or Mlh1/Atm single or double heterozygosity did not significantly affect the lifespan of the various genotypes. Mlh1/Atm double null tumors were polyclonal whereas the tumors in other genotypes were mono- or oligoclonal, demonstrating the high predisposition of thymocytes with this genotype to become malignant. Chromosomal aberrations in the tumors were localized mainly in chromosomes 12 and 15. The genomic region on chromosome 15, which contains the gene for the c-Myc oncoprotein, was commonly amplified, and elevated levels of the c-Myc protein were subsequently observed in the tumors. Our data suggest that impaired genomic instability is an important contributing factor to cancer predisposition in A-T, while oxidative stress is more important in the radiation sensitivity and growth retardation facets of this disease.


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