LB-68

Our pervious studies have demonstrated that hTOP3α, but not hTOP3β, contributes to telomere maintenance through a recombination pathway using the RNA interference (RNAi) approach. Here, we further report that the involvement of hTOP3α in chromatin maintenance, cell cycle checkpoint and possibly tumorigenesis. RNAi-mediated hTOP3α deficiency induced chromosome instability (CIN) as evidenced by both cytometry measurement and mitotic spreading experiments. Furthermore, both Chk1 and Chk2 phosphorylations are reduced in hTOP3α-knockdown cells in response to cell cycle disrupting agents. Conversely, Chk1/2 protein levels were increased in cells ectopically expressing hTOP3α. In addition to a role in cell cycle checkpoint regulation, hTOP3α was shown to be involved in tumorigenesis. Underexpression of hTOP3α was shown to increase tumorigenesis while overexpression of hTOP3α led to tumor suppression. Reduced hTOP3α expression was also observed in tumor tissues as compared to normal ones. Collectively, we proposed that hTOP3α might play a suppressive role during cancer development possibly through its guardianship on cell cycle checkpoint and chromosome stability.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA