Nudix hydrolases in Cancer Therapy
Date du début: 12 août 2013,
Date de fin: 11 août 2015
Cancer is the activation of dysfunctional pathways leading to abnormal behaviour of cells. A hallmark of cancer is genomic instability, triggered by a range of DNA lesions such as 8-oxo-G, caused by reactive oxygen species (ROS). ROS are generated by the cell’s metabolism and are crucial for its homeostasis. However, excessive ROS levels can induce DNA lesions resulting in increased mutations, fuelling genetic instability favouring carcinogenesis. Free dNTP are more easily damaged by ROS and are cleared from the nucleotide pool by dNTP pyrophosphatases and the nucleoside diphosphate linked moiety X family (Nudix) hydrolases, consisting of 22 members. These highly specialized proteins hydrolyse oxidized lesions such as 8-oxodGTP present in the nucleotide pool, thus preventing the incorporation of oxidized nucleotides into the RNA or the DNA. Cancer cells sustain abnormally high levels of ROS generated by deregulated metabolism and protein translation. Preliminary data from the host laboratory suggest that the Nudix hydrolase MTH1 is overexpressed in cancer and that cancer cells require its catalytic activity for survival. This is interesting, as normal cells do not rely on MTH1 for survival. Small molecule inhibitors from the host laboratory targeting MTH1, effectively kill transforming cells but not the parental immortalized cells. Thus, I hypothesize that the Nudix hydrolases may play important roles in cancer, and that insight into this pathway can be exploited to design novel anti-cancer strategies. The functions of a large portion of the 22 Nudix hydrolases are unknown. The objective of this project is to determine the biological and biochemical roles of all the Nudix hydrolases in cancer, including resistance and relapse, and thereby identify potential novel targets for cancer therapy and biomarkers. This will be achieved by using established technology at the host institute such as synthetic lethality screens, and by developing a novel 3D multiparametric assay
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