Electronic Thesis/Dissertation


The Role of Polo-like kinase 1 in Cell Cycle Progression after Genotoxic Insult: Consequences of Forced Checkpoint Bypass Open Access

Exposure to carcinogens significantly increases the risk of developing cancer. Occupational and environmental exposure to genotoxic agents can lead to DNA damage and carcinogenesis. Some hexavalent chromium compounds [Cr(VI)] are occupational/environmental human respiratory carcinogens. Molecularly, Cr(VI) carcinogenesis involves dysregulation of cell cycle signaling resulting in cells that become death resistant. Activation of survival pathways after DNA damage may drive carcinogenesis, and it is known that inhibitors of protein tyrosine phosphatases (PTPs) activate key survival pathways. Recently, Polo-like kinase 1 (Plk1) has been shown to play a fundamental role in the DNA damage response. Plk1 is overexpressed in a variety of tumors and its expression correlates with poor patient prognosis. Therefore, Plk1 has become a promising target for cancer therapy. Our overarching goal was to investigate the role of Plk1 in the bypass of the DNA damage checkpoint after genotoxic exposure. We utilized human lung fibroblasts (HLFs) and Saccharomyces cerevisiae to examine the role of Plk1 in promoting mitosis after DNA damage. HLF cells were treated with Cr(VI) with and without PTP inhibition. PTP inhibition bypassed the Cr(VI)-induced G2/M arrest which was associated with decreased Cdk1 Tyr15 phosphorylation, increased Plk1 activity, and the nuclear localization of Plk1. Inhibition of Plk1 activity abolished the PTP inhibitor-induced bypass of the G2/M checkpoint after Cr(VI) exposure. The Plk1 constitutively active T210D mutant was able to override Cr(VI)-induced G2/M arrest and Plk1 activation was necessary for the PTP inhibitor-induced increase in clonogenic survival after Cr(VI) exposure. Plk1 expression was able to rescue wild-type and rad52 S. cerevisiae after Cr(VI) treatment. Furthermore, our data suggest the role of Plk1 activation in enhanced DNA double strand break (DSB) repair, through an error-prone mechanism, which results in enhanced mutagenesis. Taken together, these data indicate that Plk1 is involved in the override of Cr(VI)-induced G2/M arrest, increased survival and mutagenesis at the expense of proper DNA repair which may promote neoplastic transformation. These studies further elucidate the consequences of bypassing the DNA damage checkpoint and enhance the understanding of Plk1 as a promising therapeutic target. These studies also highlight the role of Plk1 and DNA damage repair in environmental/occupational carcinogenesis.

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