The transfer of information encoded by genes in the genome to messenger RNAs (mRNAs), which are translated into proteins that control specific cellular processes, in a fundamental process in biology. Cancer cells exert exceptional control over this process and dysregulate it as needed to gain a selective growth advantage versus normal cells. One mechanism that cancers use to control the translation of mRNAs into proteins is to add chemical groups on specific amino acids in proteins that comprise the cellular translation machinery. One such modification is called ADP-ribosylation (ADPRylation). We found that cancer cells increase ADPRylation of the translation machinery by increasing the ...

Read More

The transfer of information encoded by genes in the genome to messenger RNAs (mRNAs), which are translated into proteins that control specific cellular processes, in a fundamental process in biology. Cancer cells exert exceptional control over this process and dysregulate it as needed to gain a selective growth advantage versus normal cells. One mechanism that cancers use to control the translation of mRNAs into proteins is to add chemical groups on specific amino acids in proteins that comprise the cellular translation machinery. One such modification is called ADP-ribosylation (ADPRylation). We found that cancer cells increase ADPRylation of the translation machinery by increasing the activity of an enzyme called PARP-16. This allows the cancer cells to carefully control protein production and maintain an ideal cellular state for growth called "proteostasis". In this research proposal, we propose a series of experiments to test the hypothesis that ovarian cancers control various functions of the translation machinery by enhancing the ability of PARP-16 to ADPRylate specific amino acids in proteins that comprise the cellular translation machinery. To test this hypothesis, we will explore (1) the molecular mechanisms of this regulation in ovarian cancers and (2) how this regulation enhances the growth of ovarian cancer cells and tumors. Successful completion of the proposed experiments will yield (1) new resources for the research community, (2) new insights about the molecular underpinnings of ovarian cancer, (3) new methods and approaches for studying cancer, and (4) new insights for the use of PARP-16 inhibitors in cancers with enhanced PARP-16 activity.

Read Less