Deciphering the Roles of Novel CDK4/6 Substrates in G1/S Control and Cancer Progression

The G1/S transition is a critical checkpoint in the cell cycle, controlling the decision of cells to either proceed into DNA replication or enter quiescence. Disruption of this checkpoint is a hallmark of cancer, often driven by hyperactivation of CDK4/6, which is known for its role in phosphorylating the retinoblastoma protein (Rb). However, recent evidence suggests that CDK4/6 targets other substrates beyond Rb that play important but less explored roles in regulating the G1/S checkpoint. In this project, we aim to identify and characterize novel CDK4/6 substrates and their phosphorylation patterns, exploring how these mechanisms contribute to cell cycle control and tumorigenesis. Through a combination of cutting-edge biochemical techniques and quantitative live-cell imaging, we will investigate how these new CDK4/6 substrates modulate the decision-making process during cell division in both normal and cancerous cells. The PhD candidate will have the opportunity to develop a multidisciplinary skill set, combining advanced molecular biology, cell biology, and state-of-the-art microscopy. The project will include extensive biochemical assays to define phosphorylation events, CRISPR/Cas9-mediated gene editing to study the functional impact of these substrates, and live-cell imaging to assess the dynamics of G1/S transition in real-time. Our ultimate goal is to uncover how dysregulation of these novel substrates drives aberrant cell proliferation in cancers, potentially opening up new therapeutic strategies targeting the CDK4/6 axis. The candidate will benefit from a collaborative environment, receiving mentorship across disciplines and contributing to a highly impactful area of cancer research.