TY - JOUR
T1 - All stressed out without ATM kinase
AU - Perry, J. Jefferson P.
AU - Tainer, John A.
PY - 2011/4/5
Y1 - 2011/4/5
N2 - Ataxia-telangiectasia (A-T) is a rare, neurodegenerative, inherited disease arising from mutations in the kinase A-T mutated (ATM), which promotes cell cycle checkpoints and DNA double-strand break repair. Puzzlingly, these ATM activities fail to fully explain A-T neuropathologies, which instead have links to stress induced by reactive oxygen species (ROS). However, a landmark discovery reveals an unexpected intersection of ROS and kinase signaling: ATM can be directly activated by oxidation to form a disulfide-linked dimer in a mechanism distinct from DNA damage activation. When combined with notable structural-based insights into the ATM homolog DNA-PK (DNA-protein kinase) and mTOR (mammalian target of rapamycin), these results suggest conformation and assembly mechanisms to signal oxidative stress through an ATM nodal point. These findings fundamentally affect our understanding of ROS and ATM signaling and of the A-T phenotype, with implications for altering signaling in cancer cells to increase sensitivities to current therapeutic interventions.
AB - Ataxia-telangiectasia (A-T) is a rare, neurodegenerative, inherited disease arising from mutations in the kinase A-T mutated (ATM), which promotes cell cycle checkpoints and DNA double-strand break repair. Puzzlingly, these ATM activities fail to fully explain A-T neuropathologies, which instead have links to stress induced by reactive oxygen species (ROS). However, a landmark discovery reveals an unexpected intersection of ROS and kinase signaling: ATM can be directly activated by oxidation to form a disulfide-linked dimer in a mechanism distinct from DNA damage activation. When combined with notable structural-based insights into the ATM homolog DNA-PK (DNA-protein kinase) and mTOR (mammalian target of rapamycin), these results suggest conformation and assembly mechanisms to signal oxidative stress through an ATM nodal point. These findings fundamentally affect our understanding of ROS and ATM signaling and of the A-T phenotype, with implications for altering signaling in cancer cells to increase sensitivities to current therapeutic interventions.
UR - http://www.scopus.com/inward/record.url?scp=79953855430&partnerID=8YFLogxK
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U2 - 10.1126/scisignal.2001961
DO - 10.1126/scisignal.2001961
M3 - Review article
C2 - 21467296
AN - SCOPUS:79953855430
SN - 1945-0877
VL - 4
JO - Science signaling
JF - Science signaling
IS - 167
M1 - pe18
ER -