Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia.
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.
Ziv
Shelly
S
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Brenner
Ori
O
Amariglio
Ninette
N
Smorodinsky
Nechama I
NI
Galron
Ronit
R
Carrion
Danaise V
DV
Zhang
Weijia
W
Sharma
Girdhar G
GG
Pandita
Raj K
RK
Agarwal
Manjula
M
Elkon
Ran
R
Katzin
Nirit
N
Bar-Am
Irit
I
Pandita
Tej K
TK
Kucherlapati
Raju
R
Rechavi
Gideon
G
Shiloh
Yosef
Y
Barzilai
Ari
A
D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000235:genetics*; D005784:Gene Amplification; D020022:Genetic Predisposition to Disease / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D005838:Genotype; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013953:Thymus Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D025521:Tumor Suppressor Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases