Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Tuesday Speaker Abstracts

An Integrated ATR, ATM, and mTOR Mechanical Network Controlling Nuclear Plasticity Gururaj Kidiyoor 1 , Giulia Bastianello 1 , Qingsen Li 1 , Martin Kosar 1 , Amit Kumar 2,3 , Galina V. Beznoussenko 1 , Alexandre A. Mironov 1 , Dario Parazzoli 1 , G.V. Shivashankar 4 , Jiri Bartek 5 , Michele Mazzanti 6 , Giorgio Scita 1,6 . Marco Foiani 1,6 , 1 IFOM (Fondazione Istituto FIRC di Oncologia Molecolare), Milan, Italy, 2 CSIR-Indian Insttiute of Toxicology Reseearch, Lucknow, India, 3 Academy of Scientific and Innovative Research (AcSIR), Taramani, India, 4 Mechanobiology Institute and Department of Biological Sciences, NUS, Singapore, Singapore, 5 Danish Cancer Society Research Center, Copenhagen, Denmark, 6 Università degli Studi di Milano, Milan, Italy. ATR and ATM control chromosome integrity, chromatin dynamics and cell cycle events. mTOR exhibits similarities to ATR and ATM and coordinates nutrient sensing pathways and cytoskeleton dynamics. We recently found (A.Kumar et al. Cell, 2014) that ATR, ATRIP and Chk1 associate to the nuclear envelope during S phase and prophase, and in response to mechanical stimulation of the plasma membrane. The ATR-mediated mechanical response occurs within the range of physiological forces, recovers rapidly, and is not influenced by RPA or DNA damage. ATR defective cells exhibit aberrant chromatin condensation and nuclear envelope breakdown. We found that this pathway is influence by mTOR, actin dynamics and calcium levels. We used electron microscopy to visualize the nucleus morphology of the nucleus in ATR and CHK1- defective cells and found aberrant condensation events and nuclear envelope anomalies that may contribute to micronuclei formation and chromosome fragmentation. Using mechanobiology approaches we measured the stiffness of wild type, ATR, ATM, CHK1 and mTOR defective cells and found significant differences that influence cell plasticity and interstitial migration. These and other observations implicate ATR, ATM and mTOR in the control of genome integrity, nuclear dynamics and cell plasticity and suggest the existence of an integrated mechanical network involving different PI3-kinases.

17