Human Molecular Genetics Advance Access originally published online on September 8, 2005
Human Molecular Genetics 2005 14(19):2929-2943; doi:10.1093/hmg/ddi324
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Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia
1Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel, 2Department of Veterinary Resources, the Weizmann Institute of Science, Rehovot 76100, Israel, 3Sheba Cancer Research Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52126, and Sackler School of Medicine, Tel Aviv University, Israel, 4Alec and Myra Marmot Hybridoma Laboratory, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel, 5Departments of Medicine and Genetics and Harvard Partners Center for Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, 6Department of Oncology and Radiation, Washington University, School of Medicine, St Louis, MO 63108, USA, 7Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel and 8Applied Spectral Imaging, Migdal Haemek 10551, Israel
* To whom correspondence should be addressed. Tel: +972 36409782; Fax: +972 36407643; Email: barzilai{at}post.tau.ac.il
Received June 22, 2005; Revised August 11, 2005; Accepted August 19, 2005
Ataxia–telangiectasia (A-T) is a multisystem, cancer-predisposing genetic disorder caused by deficiency of the ATM protein. 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. In contrast, 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 with thes Atm–/– single knockout. Remarkably, Atm, Mlh1 or Mlh1/Atm single or double heterozygosity did not significantly affect the life span 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, whereas oxidative stress is more important in the radiation sensitivity and growth retardation facets of this disease.
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