The role of LARP1 in nucleotide biogenesis
A proliferating cell is required to double its biomass before every cell division. As the major macromolecular component of cells is protein, it must increase its protein biogenesis machinery (i.e. ribosomes, rRNA and rNTPs) in order to increase protein content. Hence, ribosome and nucleotide biogenesis are closely coupled to protein production, especially in cancer cells where proliferation is uncontrolled. The RNA binding protein LARP1 is an important post-transcriptional regulator. In previous work, we have linked the upregulated expression of LARP1 with (adverse) outcome in ovarian, cervical and lung cancers. LARP1 controls cancer cell survival and depletion of LARP1 increases susceptibility to antimetabolite chemotherapies, such as gemcitabine. We have demonstrated that LARP1 recognises, binds and stabilises “TOP” mRNAs which are important for ribosome biogenesis. Interestingly, we have also identified mRNAs encoding nucleotide biogenesis enzymes as being bound by LARP1. We are currently developing drugs that will block LARP1. The purpose of this project is evaluate the effect of LARP1 on nucleotide biogenesis and chemotherapy sensitivity in cancer cells. This project will reveal how LARP1 modulates chemosensitivity in cancer cells and how this can be manipulated to benefit cancer patients.
Secondary supervision will be provided by Skirmantas Kriaucionis.