Off the beaten track: roles of priority unstudied proteins in cellular quiescence and ageing (360G-Wellcome-302608_Z_23_Z)

Most researchers study well-known genes that function in established processes. While such focus is rewarding, we must also study genes whose functions remain uncharacterized. Progress with unknown genes is staggeringly slow, even in well-studied organisms, presenting a bottleneck for biomedical progress. We will investigate the cellular roles of ‘priority unstudied’ genes that are widely conserved from fission yeast to humans but have not been directly studied in any organism. Our findings indicate that many of these genes exert ageing-related functions in quiescent cells, an under-studied state. We will broadly characterize these genes in yeast using multi- dimensional approaches, both unbiased and targeted, including assays for metabolic/proteomic profiles, genetic interactions, chronological lifespan, and bulk QTL mapping. We will integrate these results with existing datasets for biological-process predictions using machine learning, and actively disseminate the rich functional insights to trigger specialized follow-on research. Based on our predictions, we will perform targeted yeast experiments to deeply characterize selected proteins in the context of cellular quiescence and ageing, including any novel ageing-associated processes. In complementary analyses, we will study conserved ageing-associated proteins in the short- lived turquoise killifish. This programme offers vital groundwork to understand hitherto unstudied proteins, with the potential for discovering new ageing biology.