Dysregulation of RNA biogenesis in cancer predisposition
Synthesis of messenger RNA into protein by ribosomes is essential for all life. Ribosome deficiency underlies a range of developmental diseases, collectively known as ribosomopathies. Patients suffer life-threatening anaemia yet, paradoxically, experience 28x higher incidence of acute myeloid leukemia. Towards investigating the currently unknown mechanisms of tumorigenesis in these patients, our work has developed Drosophila models of the Diamond-Blackfan Anaemia ribosomopathy. Strikingly, loss of the ribosomal protein RpS19 drives overproliferation of blood cells and dramatic overgrowth of the haematopoietic compartment, providing evidence that ribosomal protein depletion can directly drive tumorigenic phenotypes. Through differential translation analysis we identified upregulated NEP1, an rRNA methyltransferase implicated in ribosome assembly, as a potential driver of formation of “onco-ribosomes” which we predict contribute to the overgrowth. Thus, our work seeks to determine the contribution that variant ribosomes play in disease and to identify mechanisms of ribosome biogenesis impacted by ribosomal protein deficiency, which could be used as novel biomarkers or therapeutic targets in cancer.
Olga is a postdoctoral researcher in the laboratory of Prof. Leonie Quinn in the Division of Genome Sciences and Cancer at John Curtin School of Medical Research, and a co-convener of the Developmental Biology Club. She completed her PhD under the supervision of Prof. Quinn and Prof. Hannan, investigating transcriptional control by single-stranded DNA binding proteins to regulate developmental growth. Her more recent work spans several cancer models including brain and blood cancers, to study how mechanisms of gene transcription and protein translation contribute to oncogenesis.