Publication: Polo-Like Kinase 4 Homodimerization in centrosome Functioning and cancer
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2024-08-31
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Indian Institute of Technology, Jodhpur
Abstract
Centrosomes are microtubule-based cylindrical structures that regulate cell division by spindle organization and cell signaling by generating cilia. Centrosome aberrations are frequently reported in several human diseases, including cancer, neurodevelopmental disorders, and metabolic diseases. The centrosome-specific kinase, Polo-like kinase 4 (PLK4), is a master regulator as it dictates the number and organization of new centrosomes in dividing cells. It is a serine/threonine kinase with a unique cryptic polo-box (CPB) region that undergoes homodimerization to activate its trans-autophosphorylation. In the doctoral work, we identified a cancerous variant in the PLK4 CPB region that could not homodimerize. The homodimerization mutant disrupts centrosome recruitment of an upstream regulator CEP152 at the late S-phase of the cell cycle, which affects pericentrin-dependent spindle organization. The work shows a cross-dependency between CEP152 and PLK4 homodimerization for centrosome functioning, which is disrupted in cancer. We further predicted the in-silico structure of full-length human PLK4, which allowed us to repurpose new classes of FDA-approved drugs, possibly targeting PLK4 through the unique CPB region. Centrosome/basal body defects are linked to the metabolic disorder Type-2 Diabetes Mellitus (T2DM), and epidemiological studies suggest enhanced cancer risk in T2DM patients. We utilized computational approaches to identify genetic biomarkers with potential prognostic value in T2DM patients susceptible to cancer. Overall, the doctoral work contributed to gaining mechanistic insights into centrosome organization and its implications in developing therapeutic strategies for human diseases, including cancer and T2DM.
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Kasera, Harshita(2019).Polo-Like Kinase 4 Homodimerization in centrosome Functioning and cancer (Doctor's thesis).Indian Institute of Technology, Jodhpur