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Ataxia-telangiectasia and related diseases

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Abstract

Appropriate cellular signaling responses to DNA damage and the ability to repair DNA are fundamental processes that are required for organismal survival. Ataxia-telangiectasia (A-T) is a rare neurodegenerative disease that results from defective DNA damage signaling. Understanding the molecular basis of A-T has provided many critical insights into the cellular response to DNA double-strand breaks (DSBs). A-T is a syndrome that shows pronounced neurodegeneration of the nervous system coincident with immune deficiency, radiosensitivity, and cancer proneness. A-T results from inactivation of the A-T mutated (ATM) kinase, a critical protein kinase that regulates the response to DNA-DSBs by selective phosphorylation of a variety of substrates. Therefore, understanding the ATM signaling program has important biological ramifications for nervous system homeostasis. Underscoring the importance of the DNA-DSBs response in the nervous system are other diseases related to A-T that also result from defects in this signaling pathway. In particular, defects in the DNA damage sensor, the Mre11-RAD50-NBS1 complex, also lead to syndromes with neurological deficits and overlapping phenotypes to A-T. Collectively, these diseases high light the critical importance of appropriate responses to DNA-DSBs to maintain homeostasis in the nervous system.

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  1. Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, 38105, Memphis, TN

    Pierre-Olivier Frappart & Peter J. McKinnon

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Frappart, PO., McKinnon, P.J. Ataxia-telangiectasia and related diseases. Neuromol Med 8, 495–511 (2006). https://doi.org/10.1385/NMM:8:4:495

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