Focus of Research:
Currently Attending:
Boston University
Co-Authors Vladimir Gabai; Michael Sherman
The Biology of Molecular Chaperones23-28 May, Dubrovnik, Croatia (EMBO meeting)23 -28 May, 2009 | Dubrovnik, Croatia AbstractKnockout of Hsp72 was demonstrated to promote chromosomal instability and increase radiation sensitivity of mouse fibroblasts. Here we report that downregulation of Hsp72 leads to suppression of a specific branch of the DNA damage response that facilitates DNA repair following genotoxic insults, i.e. reduced accumulation of the phosphorylated form of histone H2AX (gH2AX). This inhibition was due to decreased expression of H2AX as well as higher rate of gH2AX dephosphorylation. Formation of gH2AX and MDC1 radiation-induced foci was partially impaired in Hsp72-depleted cells, which in turn enhanced DNA damage, resulting in sensitization of cells to gIR and doxorubicin. These effects of Hsp72 depletion were dependent on activation of the p53/p21 signaling pathway. Overall, permanent activation of the p53/p21 signaling in Hsp72-depleted cells specifically impaired the gH2AX pathway of the DNA damage response, enhanced DNA damage following genotoxic insults, and led to further stimulation of the p53/p21 pathway, thus creating a positive feedback loop. The resulting strong induction of p21 precipitated senescence following exposure to DNA damaging agents, thus accounting for greater sensitivity to genotoxic stresses. M23 -28 May, 2009 | Dubrovnik, Croatia -28 May, 2009 | Dubrovnik, Croatia