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Mechanobiology of Disease
Tuesday Speaker Abstracts
17
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.