64 / 129
Mechanobiology of Disease
Poster Abstracts
59
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.