Abstract
BackgroundMaintenance of genome integrity is crucial for the propagation of the genetic information. Cdt1 is a major component of the pre-replicative complex, which controls once per cell cycle DNA replication. Upon DNA damage, Cdt1 is rapidly targeted for degradation. This targeting has been suggested to safeguard genomic integrity and prevent re-replication while DNA repair is in progress. Cdt1 is deregulated in tumor specimens, while its aberrant expression is linked with aneuploidy and promotes tumorigenesis in animal models. The induction of lesions in DNA is a common mechanism by which many cytotoxic anticancer agents operate, leading to cell cycle arrest and apoptosis.Methodology/Principal FindingIn the present study we examine the ability of several anticancer drugs to target Cdt1 for degradation. We show that treatment of HeLa and HepG2 cells with MMS, Cisplatin and Doxorubicin lead to rapid proteolysis of Cdt1, whereas treatment with 5-Fluorouracil and Tamoxifen leave Cdt1 expression unaffected. Etoposide affects Cdt1 stability in HepG2 cells and not in HeLa cells. RNAi experiments suggest that Cdt1 proteolysis in response to MMS depends on the presence of the sliding clamp PCNA.Conclusion/SignificanceOur data suggest that treatment of tumor cells with commonly used chemotherapeutic agents induces differential responses with respect to Cdt1 proteolysis. Information on specific cellular targets in response to distinct anticancer chemotherapeutic drugs in different cancer cell types may contribute to the optimization of the efficacy of chemotherapy.
Highlights
Cancer is a complex, multifactorial disease with both genetic and environmental factors involved in its etiology
In order to investigate whether routinely used anticancer chemotherapeutic agents activate the Cdt1 proteolysis similar to UV, anticancer agents with distinct mechanisms of action were screened for their ability to target the licensing factor Cdt1 in different human cancerous cell lines
We first examined whether Cdt1 targeting occurs in response to cisplatin known to introduce DNA adducts that mainly result in intrastrand cross-links
Summary
Multifactorial disease with both genetic and environmental factors involved in its etiology. Whereas Cdt targeting for degradation in response to UV and c-irradiation is relatively well understood, little is known about Cdt proteolytic degradation in cells treated with commonly used chemotherapeutic anticancer agents, which target DNA. These drugs are among the most effective in clinical practice and have produced significant increases in the survival of patients with cancer when used in combination with drugs that have different mechanisms of actions. The identification of new cellular targets will help understand the requirements for efficient responses by different types of cancer cells and will provide information for a better understanding of the chemotherapeutic drug’s cellular mechanisms of action. The induction of lesions in DNA is a common mechanism by which many cytotoxic anticancer agents operate, leading to cell cycle arrest and apoptosis
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