Novel roles for ribonucleases in cell proliferation: understanding the role of RNA stability in control of cell proliferation

Regulation of cell proliferation is of crucial importance to all multicellular organisms. Cells must proliferate throughout development in order for the organism to grow from an egg to an adult. Proliferation must also occur to repair damaged areas during the process of wound healing. Control of proliferation is vitally important to allow individual animals and their constituent organs to grow to reach and not exceed their correct sizes, as well as to maintain symmetry between the left and right sides of an animal. Uncontrolled cell proliferation is a hallmark of cancer with many genes involved in growth and proliferation implicated in cancer progression.

Using fruit flies as a model organism, we have recently discovered that cell proliferation can be regulated by an enzyme named Dis3L2. This enzyme is known to destroy messenger RNA molecules (mRNAs) which instruct the cell to make particular proteins. By comparing mutant fruit flies lacking Dis3L2 with normal individuals, we have found that lack of Dis3L2 results in wings that are much larger than normal. The wings grow from larval wing imaginal discs, which are also much larger in the mutant. Our results are particularly interesting because mutations in the equivalent human gene, DIS3L2, result in Perlman syndrome and susceptibility to a kidney cancer called Wilms’ tumour. Perlman syndrome is an overgrowth condition where affected children display pre-natal gigantism and abnormal enlargement of organs (e.g. kidneys). Therefore mutations in Dis3L2 in both fruit flies and humans result in the overgrowth of cells within some organs, showing an excellent conservation of this biological pathway between these organisms and demonstrating the usefulness of fruit flies to understand this disease.

This project aims to understand the role of RNA stability in control of cell proliferation. The project will use a comprehensive state-of-the-art toolset of techniques (including RNA-seq, molecular biology, genetics, bioimaging techniques and bioinformatics) to identify the RNA targets of this ribonuclease as well as the cellular pathways involved. The model organism Drosophila will first be used to establish the regulatory mechanisms involved which will then be followed up by analysis of related pathways in human cells with proliferation or cancer-associated phenotypes. This project will provide valuable insights into a new cellular pathway which can be used in the development of new disease therapeutics.