Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis.
BACKGROUND
In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation.


METHODS
Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons.


RESULTS
Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis.


CONCLUSIONS
Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.
Su
Fengtao
F
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China.
Smilenov
Lubomir B
LB
Ludwig
Thomas
T
Zhou
Libin
L
Zhu
Jiayun
J
Zhou
Guangming
G
Hall
Eric J
EJ
D022981:Allelic Imbalance / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics* / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000528:radiation effects; D020552:Comet Assay; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000528:radiation effects; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000528:radiation effects; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000528:radiation effects
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases