IISER Mohali, Knowledge city, Sector 81, SAS Nagar, Manauli PO 140306

Microtubule Targeting Agents; Mechanisms and Implications for Cancer Chemotherapy

Dr. Ankit Rai (Faculty Candidate, Utrecht University, the Netherlands)

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Abstract:
Microtubules play important roles in several cellular functions including cell division, cell differentiation, cell migration, intracellular trafficking, and cell signaling cascades. Microtubules are important drug target during cancer chemotherapy and neurodegenerative disease treatment. Microtubules are polymers of tubulin dimers, and conformational transitions in the microtubule lattice drive microtubule dynamic instability and affect various aspects of microtubule function. The exact nature of these transitions and their modulation by anti-cancer drugs such as Taxol and epothilone, which can stabilize microtubules but also perturb their growth, are poorly understood. I directly visualized the action of fluorescent Taxol and epothilone derivatives and showed that microtubules can transition to a state that triggers cooperative drug binding to form regions with altered lattice conformation. Such regions emerge at growing microtubule ends that are in a pre-catastrophe state and inhibit microtubule growth and shortening. Electron microscopy and in vitro dynamics data indicated that taxane accumulation zones represent incomplete tubes that can persist, incorporate tubulin dimers and repeatedly induce microtubule rescues. Thus, taxanes modulate the material properties of microtubules by converting destabilized growing microtubule ends into regions resistant to depolymerization (Rai et al., 2020, Nature Materials). In addition, very recently, I showed that such drug-induced defects led to frequent catastrophes and induced protofilament number mismatch. Our data suggest that structural defects within microtubule lattice can exert effects that can propagate over long distances and affect the dynamic state of the microtubule end (Rai et al., 2021, PNAS, manuscript accepted). Further, using in vitro reconstitution-based microtubule dynamic assays, I showed that the mammalian kinesin-4 KIF21B is a processive motor that can accumulate at microtubule plus ends and induce pausing. A few KIF21B molecules are sufficient to induce strong growth inhibition of a microtubule plus-end in vitro (van Riel* and Rai* et al., 2017, Elife *Equal first author).

Meeting ID: 944 6387 0062
Passcode: 402928
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