Molecular basis of clathrin-mediated stabilization of microtubules for chromosome segregation

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The precise regulation of microtubule dynamics and stability during mitosis is critical for accurate chromosome segregation and genome stability. Indeed, the hyperstabilization of microtubules frequently observed in cancer cells during mitosis induces chromosome missegregation and chromosomal instability (CIN), important factors that drive tumour progression. Despite this knowledge, we continue to have a poor understanding of the players and mechanisms by which cells regulate microtubule stability during mitosis. Clathrin, widely known for its well-studied role as a vesicle coating protein for endocytosis and vesicle trafficking, has recently been shown to play an important yet independent role in microtubule stabilization during mitosis. Clathrin associates with the mitotic spindle and stabilizes microtubules required for efficient chromosome alignment. The mechanisms by which clathrin stabilizes microtubules, however, have remained elusive. Hence the overall objective of this proposal is to elucidate how clathrin and its mitotically-associated protein complex promotes microtubule stability. We have recently discovered a novel microtubule stabilizing protein, GTSE1, and identified its stabilization mechanism and the impact of its often-seen deregulation in cancer cells on CIN. Preliminary data suggests that clathrin may directly recruit GTSE1 to spindles in an analogous manner to clathrin-adaptor protein interactions: via clathrin adaptor binding sites within the N-terminal beta propeller of clathrin heavy chain and conserved adaptor-like motifs in GTSE1. This exciting finding has inspired this proposal, in which we aim to investigate the mechanisms and role of clathrin recruitment of GTSE1 to the spindle, the structural nature of the clathrin-stabilization complex on microtubules, and more broadly the contribution of clathrin-adaptor protein-like interactions to microtubule stability. With these studies we aspire to provide a mechanistic explanation of how clathrin stabilizes microtubules to ensure chromosome segregation, leading to deeper insights to the regulation of mitotic microtubule stability and its deregulation in cancer.