DNA damage-induced signalling in ataxia-telangiectasia and related syndromes.
ATM, the protein mutated in the human genetic disorder ataxia-telangiectasia, functions by responding to radiation damage to DNA, primarily DNA double strand breaks (dsb), to reduce the risk of genome instability, cancer and neurodegeneration. ATM is rapidly activated as an existing protein to phosphorylate a number of downstream proteins that are involved in DNA repair and cell cycle checkpoint activation. While the exact mechanism of activation of ATM has not been determined, it is now evident that it relies heavily on the Mre11 complex (Mre11/Rad50/Nbs1) and a series of post-translational events for this activation. The Mre11 complex acts as a sensor for the break, recruits ATM to this site where it is autophosphorylated and then is capable of phosphorylating substrates that participate in DNA repair and cell cycle control. A greater understanding of how ATM is activated and functions through different signalling pathways is paramount to devising therapeutic strategies for the treatment of A-T patients. This knowledge can also be used to advantage in sensitizing cells to radiation and ultimately deriving novel therapeutic approaches for the treatment of cancer.
Lavin
Martin F
MF
Queensland Institute of Medical Research, Brisbane, Australia; School of Medicine, The University of Queensland, Brisbane, Australia. martin@qimr.edu.au
Kozlov
Sergei
S
D001260:Ataxia Telangiectasia / Q000209:etiology* / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020752:Neurocutaneous Syndromes / Q000209:etiology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases