Erratic expression of DNA polymerases by beta-amyloid causes neuronal death.
An ectopic reentrance into the cell cycle with ensuing DNA replication is required for neuronal apoptosis induced by beta-amyloid. Here, we investigate the repertoire of DNA polymerases expressed in beta-amyloid-treated neurons, and their specific role in DNA synthesis and apoptosis. We show that exposure of cultured cortical neurons to beta-amyloid induces the expression of DNA polymerase-beta, proliferating cell nuclear antigen, and the p49 and p58 subunits of DNA primase. Induction requires the activity of cyclin-dependent kinases. The knockdown of the p49 primase subunit prevents beta-amyloid-induced neuronal DNA synthesis and apoptosis. Similar effects are observed by knocking down DNA polymerase-beta or by using dideoxycytidine, a preferential inhibitor of this enzyme. Thus, the reparative enzyme DNA polymerase-beta unexpectedly mediates a large component of de novo DNA synthesis and apoptotic death in neurons exposed to beta-amyloid. These data indicate that DNA polymerases become death signals when erratically expressed by differentiated neurons.
Copani
Agata
A
Department of Pharmaceutical Sciences, University of Catania, Catania, 95125, Italy. acopani@katamail.com
Sortino
Maria Angela
MA
Caricasole
Andrea
A
Chiechio
S
S
Chisari
Mariangela
M
Battaglia
Giuseppe
G
Giuffrida-Stella
Anna Maria
AM
Vancheri
Carlo
C
Nicoletti
Ferdinando
F
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C074636:amyloid beta-protein (25-35); D004259:DNA-Directed DNA Polymerase