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Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

Citation

Ambrose, M and Gatti, RA, Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions, Blood, 121, (20) pp. 4036-4045. ISSN 0006-4971 (2013) [Refereed Article]


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Copyright Statement

Copyright 2013 The American Society of Hematology

DOI: doi:10.1182/blood-2012-09-456897

Abstract

In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients-children and adults alike-which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

Item Details

Item Type:Refereed Article
Keywords:ATM, DNA repair, mitochondria
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Anthropological Genetics
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Endocrine Organs and Diseases (excl. Diabetes)
Author:Ambrose, M (Dr Mark Ambrose)
ID Code:87154
Year Published:2013
Web of Science® Times Cited:87
Deposited By:Medicine (Discipline)
Deposited On:2013-11-08
Last Modified:2014-07-25
Downloads:0

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