Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia

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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2929-2943
Number of pages15
JournalHuman Molecular Genetics
Issue number19
StatePublished - Oct 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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