EFFECT OF HDAC INHIBITORS ON THE ROLE OF Gadd45 IN THE DNA REPAIR
M.V. Igotti,1 E.A. Filippova, O.O. Gnedina, S.B. Svetlikova
Institute of Cytology RAS, St. Petersburg;
1 e-mail: marie.igotti@gmail.com
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 Gadd45α protein modulation. Our results indicate that suppression of Gadd45a 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 Gadd45a 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.
Key words:
Gadd45α, histone deacetylase inhibitors (HDIs), DNA repair, oncogenes E1A and cHa-ras,
transformed cells
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