Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Poster Abstracts

46-POS Board 46 Mechanobiology in DNA Damage Response Qingsen Li , Gururaj Kidiyoor, Martin Kosar, Giulia Bastianello, Marco Foiani. IFOM, Milan, Milano, Italy. The ATR protein kinase controls the DNA damage response (DDR) [1], with ATM, Chk1 and Chk2. DDR genes are often mutated in cancer cells and act as an anti-cancer barrier in response to oncogenic stimuli [2, 3]. ATR is essential and protects the integrity of replicating chromosomes [4, 5], prevents fragile site expression [6, 7] and aberrant condensation events [6, 8]. The Foiani laboratory recently found that ATR associates with the nuclear envelope during S phase and prophase and in response to osmotic or mechanical stress [9]. However, the molecular mechanism and functional relevance of ATR-mediated mechanical response remain unclear. To address these questions, we will employ and develop various multidisciplinary approaches including state-of-the-art Atomic Force Microscopy (AFM), micropatterned protein substrate, novel microfluidic device and accompanied with advanced molecular biology techniques in order to quantitatively and systematically explore the ATR mediated mechanotransduction. Our preliminary results showed that the stiffness of ATR, ATM, CHK1 and mTOR defective cells are significantly different compared to wild type, which influence cell plasticity and interstitial migration. Furthermore, AFM experiments revealed that ATR defective cells have compromised nuclei, which failed to sustain mechanical stress. 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.

59