Cell cycle activation linked to neuronal cell death initiated by DNA damage.
Increasing evidence indicates that neurodegeneration involves the activation of the cell cycle machinery in postmitotic neurons. However, the purpose of these cell cycle-associated events in neuronal apoptosis remains unknown. Here we tested the hypothesis that cell cycle activation is a critical component of the DNA damage response in postmitotic neurons. Different genotoxic compounds (etoposide, methotrexate, and homocysteine) induced apoptosis accompanied by cell cycle reentry of terminally differentiated cortical neurons. In contrast, apoptosis initiated by stimuli that do not target DNA (staurosporine and colchicine) did not initiate cell cycle activation. Suppression of the function of ataxia telangiectasia mutated (ATM), a proximal component of DNA damage-induced cell cycle checkpoint pathways, attenuated both apoptosis and cell cycle reentry triggered by DNA damage but did not change the fate of neurons exposed to staurosporine and colchicine. Our data suggest that cell cycle activation is a critical element of the DNA damage response of postmitotic neurons leading to apoptosis.
Research Resources Branch, Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. inna.kruman@sunhealth.org
Inna I
II
Kruman
Robert P
RP
Wersto
Fernando
F
Cardozo-Pelaez
Lubomir
L
Smilenov
Sic L
SL
Chan
Francis J
FJ
Chrest
Roland
R
Emokpae
Myriam
M
Gorospe
Mark P
MP
Mattson
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006710:Homocysteine / Q000494:pharmacology; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D006710:Homocysteine; D005047:Etoposide; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D003078:Colchicine; D008727:Methotrexate