| Abstrakt: |
Histone deacetylase inhibitors (HDIs) cause irreversible cell cycle arrest and senescence of transformed E1A + Ras cells. The HDI sodium butyrate (NaB) causes a violation of DNA repair and, as a consequence, phosphorylation of DNA breaks marker histone H2AX. It is shown that the Gadd45 family proteins play a role in regulation of proliferation, apoptosis, and repair. In the present work, we studied the effect of NaB on repair through Gadd45α protein modulation. Our results obtained using Gadd45-deficient cells demonstrated that Gadd45 suppression results in a decrease in the efficiency of DNA repair (both basal and in the presence of NaB). However, NaB-induced suppression of DNA repair is decreased in Gadd45-expressing cells, which is probably a consequence of NaB-dependent Gadd45 accumulation in the nucleus and redistribution of its oligomeric forms. As a consequence, a change in the type of Gadd45 interaction with partner proteins (involved in regulation of proliferation and repair) occurs; this, in turn, results in inhibition of the processes of impaired DNA restoration. NaB amplified the interaction of Gadd45 with p21/Waf1 protein, thereby reducing the amount of the p21/Waf1 in complex with PCNA. Thus, accumulation of DNA breaks due to a decreased efficiency of repair occurs in the absence of Gadd45, while HDI-induced activation of Gadd45 promotes restoration of impaired DNA. DNA damages induced with HDIs or genotoxic agents could not be repaired under the lack of Gadd45. As a consequence, Gadd45 deficient transformed cells initiate apoptotic death program. [ABSTRACT FROM AUTHOR] |
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