[EFFECT OF HDAC INHIBITORS ON THE ROLE OF Gadd45 IN THE DNA REPAIR].
Histone deacetylase inhibitors (HDIs) causes irreversible cell cycle arrest and senescence of E1A+Ras transformed cells. HDI sodium butyrate (NaB) affects the DNA repair and consequently modulates the phosphorylation of DNA breaks marker histone H2AX. For Gadd45 family proteins shown the role in regulation of cell proliferation, apoptosis and DNA repair. In the present paper, we studied the effect of NaB on the DNA repair through Gadd45a protein modulation. Our results indicate that suppression of Gadd45α reduces the DNA repair efficiency, in both basal, and NaB-dependent. However NaB-induced supression of DNA repair is reduced in Gadd45-expressing transformed cells. This is the result of Gadd45α accumulation in the nucleus and redistribution of oligomeric forms of Gadd45 under NaB treatment. This results in changing of Gadd45α interaction with proteins involved in the cell cycle progression and DNA repair regulation. NaB amplified the interaction of Gadd45 with p21/Waf1 protein, thereby reducing the amount of the p21/Waf1 in complex with PCNA. Thus, in the absence Gadd45α the amount of DNA breaks accumulates due to the reduced efficiency of repair, while HDIs dependent induction of Gadd45α promotes the DNA repair. DNA damages induced with HDIs or genotoxic agents could not be repaired under the lack of Gadd45α. As a result Gadd45 deficient transformed cells initiate apoptotic death program.
M V
MV
Igotti
E A
EA
Filippova
O O
OO
Gnedina
S B
SB
Svetlikova
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D020552:Comet Assay; D004260:DNA Repair / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
D017500:Adenovirus E1A Proteins; D002087:Butyrates; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009687:Nuclear Proteins; D018631:ras Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins