**3.4 Radiosensitivity and increased cancer risk**

Several DDR pathways contribute to the increased cancer risk seen in A-T patients. The inability of A-T cells to coordinate DNA repair with other DDR pathways can leave unrepaired genomic injuries and elevate the number of mutations in cells—including perilous DSBs—rendering cells highly sensitive to ionizing

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*The Role of the DNA Damage Response in Ataxia-Telangiectasia Syndrome*

does not trigger apoptosis when ATM is absent or dysfunctional.

radiation. Lack of ATM permits these mutations to escape cell cycle checkpoints control and be transmitted to daughter cells, further contributing to tumorigenesis. This process can continue unchecked, as the genomic instability that it produces

One of the most common malignancies in A-T patients is breast cancer [132]. Even heterozygous individuals bearing debilitating mutations in just one of the ATM genes also have increased breast cancer incidence. While many DDR components are likely to participate in breast cancer tumorigenesis, the loss of the direct control that ATM exerts over BRAC1 is likely one of the major contributing factors. Lymphomas of B-cell origin and leukemia of T-cell origin are also very common in A-T patients, as unrepaired programmed DSBs persisting in developing T and B cells

Both male and female A-T patients show infertility due to abnormal meiosis progression. During meiosis, ATM controls the number of DSBs created by SPO11 and ensures their even distribution in the genome [134]. This is achieved by recruiting ATM to SPO11-generated DSBs, which inhibits the formation of further cuts in the vicinity of break sites. Mice models have shown a meiotic arrest in prophase I, faulty synapsis, and chromosome fragmentation leading to massive germ cell loss [107, 135], suggesting that the loss of ATM's roles during meiosis is the underlying

A-T patients can suffer from insulin resistance and thus, have a higher risk of developing diabetes, a clinical feature that they share with carriers of the disease. The cause for this phenotype is likely to be multifactorial, but it is well-defined that ATM phosphorylates several targets—e.g., translation regulation 4E-BP1—in response to insulin [25]. Furthermore, a lack of fully functional ATM correlates with an inhibition of IRS1 (insulin receptor substrate 1) and low levels of IGF1-R (insulin-like growth factor1 receptor), suggesting possible mechanisms causing this

While much progress has been made to understand A-T at the molecular level, there are still important questions that remain unanswered. This is especially true for the cerebellar neurodegeneration observed in A-T patients, where unknown tissuespecific factors may be at play. The genesis and the extent of some of the A-T clinical features are likely to be the result of interwoven relationships between many pathways and pathologies described in here and hence, elucidating their connections will be crucial to fully understand the disease and develop effective tools for its treatment.

This manuscript was funded and supported by the Smith Chair in Biology at the

*DOI: http://dx.doi.org/10.5772/intechopen.84902*

can often be the substrate of translocations [133].

**3.5 Other clinical features**

cause of infertility in A-T patients.

clinical feature [94, 136, 137].

**4. Conclusion**

**Acknowledgements**

University of St. Thomas.

I have no conflict of interest to declare.

**Conflict of interest**
