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Functional consequences of ATM sequence variants for chromosomal radiosensitivity
Sara Gutiérrez-Enríquez1, Marie Fernet, Thilo Dörk
1DNA Repair Group, International Agency for Research on Cancer, Lyon, France.
Genes, Chromosomes & Cancer
|April 22, 2004
Summary
Specific ATM gene alterations, including heterozygous mutations and variant alleles, increase in vitro chromosomal radiosensitivity. This suggests ATM gene variants may impact DNA repair and cellular response to radiation.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- The ATM (ataxia-telangiectasia mutated) protein is crucial for DNA double-strand break repair.
- The link between ATM gene single-nucleotide polymorphisms (SNPs) and cancer risk or radiosensitivity requires further investigation.
Purpose of the Study:
- To investigate the functional impact of specific ATM SNPs on in vitro radiosensitivity.
- To assess radiosensitivity using micronuclei (MN) formation in lymphoblastoid cell lines.
Main Methods:
- Lymphoblastoid cell lines from breast cancer (BC) patients, ataxia-telangiectasia (A-T) patients, A-T heterozygotes (A-T het), and normal individuals were used.
- Cells were exposed to ionizing radiation (IR), and MN formation was quantified.
- Specific ATM SNPs, including 2572T>C and 3161C>G, were analyzed in BC cell lines.
Main Results:
- BC, A-T het, and A-T cell lines exhibited significantly higher MN formation post-IR compared to normal cell lines.
- The linked 2572T>C and 3161C>G variants in BC lines were associated with increased MN formation.
- Elevated MN levels were independent of constitutive ATM mRNA levels in these cell lines.
Conclusions:
- Alterations in the ATM gene, including heterozygous mutations and specific variant alleles (2572C, 3161G), are linked to increased in vitro chromosomal radiosensitivity.
- These ATM variants may impair DNA repair by interfering with ATM protein function, potentially in a dominant-negative manner.