Abstract
Chromosome instability is hallmark of most human cancers. DNA damaging agents increase the probability that whole chromosome or large fraction of chromosome are gained or lost during cell division. The consequence of chromosome instability is an imbalance in the number of chromosome per cell (aneuploidy) and an enhanced rate of loss of heterozygosity. Recently, we have demonstrated that phenyl hydroquinone (PHQ), a hepatic metabolite of Ames-negative carcinogen o-phenylphenol, efficiently induced aneuploidy in yeast. We further found that PHQ bound to and interfered with the depolymerization of tubulin in vitro and arrested the cell cycle at G1 and G2/M. We argued that PHQ damaged tubulin to cause mis-segregation of chromosome by delaying cell-cycle progression through mitosis, and as a consequence caused aneuploidy. In an effort to get precise insight of the action of PHQ, we observed that 1) Irregular bud formation by PHQ triggered yeast morphogenesis checkpoint, which arrested cell cycle at G2/M, 2) PHQ stabilized Swe1 protein (human Wee1 homolog), keeping Cdc2/CycB complex inactive thus cell cycle at G2/M transition, 3) swe1 mutation abolished the PHQ-induced aneuploidy, and 4) PHQ induced Hog1 (human p38 MAPK homolog) phospholyration, by which Swe1 can be stabilized. When human HCT116 culture cells are treated with PHQ, phospholyration of human p38, ATM/ATR dependent stabilization of p53, and increase of aneuploidy were observed. Thus, PHQ can activate MAPK and p53 pathway, arrest cell cycle at G2/M boundary, and as a consequence, lead aneuploidy both in yeast and human cells.
