Maintenance and dynamic of the chromatin structure in Trypanosoma cruzi

FLAWIA MIRTHA M; ALONSO GUILLERMO D; MEYER CRISTIAN; VILCHEZ LARREA SALOMÉ C; FASSOLARI MATÍAS; TORRES HECTOR N; FERNANDEZ VILLAMIL SILVIA H

San Diego, California, USA

Congreso; Experimental Biology Annual Meeting; 2008

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0pt; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US; mso-fareast-language:EN-US;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 85.05pt 70.85pt 85.05pt; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Dynamic structural changes on the chromatin occur throughout the cell cycle. These changes range from local ones, necessary for transcriptional regulation and DNA damage repair machinery accessibility, to global changes necessary for chromosome segregation. We demonstrated that the poly(ADP-ribose)polymerase from T. cruzi (TcPARP) is strongly activated by nicked DNA and attaches polymers of ADP-ribose (PAR) to itself and to T. cruzi histones. We assayed several DNA damaging agents that trigger different DNA repair mechanisms and confirmed an increase in PAR synthesis in every case. However, when the induced damage led to cell death, the amount of PAR detected decreased. To study in depth the chromatin remodeling we cloned two T. cruzi HATs (TcHAT1 and TcElp3). TcElp3 failed to rescue a thermosensitive mutant yeast strain. We also analyzed the expression and localization of TcHAT1 and TcElp3 by using specific antibodies. We also analyzed the effect of HDACs inhibitors Trichostatin A (TSA) and sodium butyrate on epimastigotes. When parasites were treated with 50 nM TSA strong proliferation inhibition was observed and a sub G1 peak appeared on DNA histogram when analyzed by flow cytometry. This evidence not only supports a physiological relevance of chromatin remodeling in Trypanosoma cruzi but also opens new insights in drug therapy against Chagas´ disease. Supported by CONICET, FONCYT and UBA-Argentina.