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Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations
1Department of Virology, The National Children's Medical Research Center, Tokyo, Japan.
Abstract:
Ataxia telangiectasia (AT) carrier-derived lymphoblastoid cell lines (AT-LCLs/hetero) with suboptimal ATM protein expression were examined for the regulation of radiosensitivity, apoptosis, and mitotic spindle checkpoint in response to DNA-damaging agents. Although AT-LCLs/hetero showed intermediate radiation sensitivity, as determined by clonogenic assay, they were resistant to early-onset apoptosis, as much as AT patient-derived LCLs (AT-LCLs/homo). Furthermore, two of three AT-LCLs/hetero showed defective mitotic spindle checkpoint control in response to X-ray irradiation, which is a recently characterized biological feature in AT-LCLs/homo. Our findings indicate that carriers of ATM mutation have biological abnormalities due to haploinsufficiency of ATM protein or dominant-negative effect of mutant ATM protein. Thus, although it is still controversial whether ATM mutation carriers are at higher risk for cancer during adulthood, our findings based on in vitro biological indicators support the notion that at least some of such carriers are at a higher risk for cancer development than those without ATM mutation. Our findings may help to reevaluate epidemiological studies on cancer susceptibility in AT carriers.
Insights
Ataxia telangiectasia (AT) carriers with suboptimal ATM protein expression exhibit biological abnormalities. These findings suggest AT carriers may have an increased cancer risk compared to non-carriers.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Ataxia telangiectasia (AT) is a rare autosomal recessive disorder caused by mutations in the ATM gene.
- ATM protein plays a crucial role in DNA damage response, cell cycle checkpoint control, and maintaining genomic stability.
- Understanding the biological consequences of heterozygous ATM mutations is important for assessing cancer risk in carriers.
Purpose of the Study:
- To investigate the radiosensitivity, apoptosis regulation, and mitotic spindle checkpoint function in lymphoblastoid cell lines derived from AT carriers (AT-LCLs/hetero).
- To determine if carriers of ATM mutations exhibit distinct cellular responses to DNA-damaging agents compared to healthy individuals and AT patients.
- To explore the implications of these biological abnormalities for cancer susceptibility in ATM mutation carriers.
Main Methods:
- Utilized lymphoblastoid cell lines derived from AT carriers (AT-LCLs/hetero) with reduced ATM protein expression.
- Assessed radiosensitivity using clonogenic assays.
- Evaluated apoptosis induction and mitotic spindle checkpoint control following exposure to DNA-damaging agents, specifically X-ray irradiation.
Main Results:
- AT-LCLs/hetero displayed intermediate radiosensitivity but were resistant to early-onset apoptosis, similar to AT patient-derived LCLs (AT-LCLs/homo).
- Two out of three AT-LCLs/hetero examined showed defective mitotic spindle checkpoint control after X-ray irradiation.
- These cellular defects are attributed to ATM haploinsufficiency or a dominant-negative effect of the mutant ATM protein.
Conclusions:
- ATM mutation carriers exhibit significant biological abnormalities, including impaired DNA damage response and checkpoint control.
- These in vitro findings support the hypothesis that ATM mutation carriers may have an elevated risk of cancer development.
- The study suggests a need to re-evaluate epidemiological studies on cancer susceptibility in AT carriers based on these biological indicators.