The ATM (Ataxia-telangiectasia mutated) kinase is one of the major players of the DNA damage response and its mutation causes the development of the Ataxia-telangiectasia genetic disorder (A-T). ATM belongs to the family of phosphatidylinositol 3-kinase-related kinases, which also includes TRRAP, SMG1, ATR, DNA-PK and mTOR. ATM, ATR and DNA-PK collaborate to preserve genome integrity in the face of DNA double strand breaks (ATM, DNA-PK) and replication stress (ATR). Recent observations are expanding the roles of these kinases outside the nucleus. Accordingly, ATM and ATR are activated in the absence of DNA damage by multiple stress conditions. Our group previously showed that ATR is activated by mechanical stress and localizes to the nuclear envelope; moreover, recent unpublished observations in our lab suggest that ATR influences cell mechanics regulating nuclear plasticity. Here we investigate the function of ATM in relation to cell mechanics using a variety of techniques to study the mechanical properties of the cells and their ability to migrate across constrictions. We found that ATM depletion increases cell stiffness and impairs cell survival during interstitial migration. Moreover, ATM is activated in cells subjected to nuclear deformation during the squeezing across constrictions in 3D migration. By mass spectrometry analysis we identified a plethora of proteins involved in the regulation of cytoskeleton and cell structure that interact with ATM, many of which are subjected to future investigations. Altogether these observations suggest that ATM plays a role in the control of cell plasticity and migration, possibly through the regulation of cytoskeletal components.
THE ROLE OF ATM IN THE REGULATION OF CELL MECHANICS / G. Bastianello ; added supervisor: H. Arakawa ; supervisor: M. Foiani. - Milano : Università degli studi di Milano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2017 Mar 02. ((28. ciclo, Anno Accademico 2016.
|Titolo:||THE ROLE OF ATM IN THE REGULATION OF CELL MECHANICS|
|Data di pubblicazione:||2-mar-2017|
|Parole Chiave:||ATM, cyoskeleton ; cell mechanics ; migration ; AID ; gene conversion ; double-strand break|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Citazione:||THE ROLE OF ATM IN THE REGULATION OF CELL MECHANICS / G. Bastianello ; added supervisor: H. Arakawa ; supervisor: M. Foiani. - Milano : Università degli studi di Milano. DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2017 Mar 02. ((28. ciclo, Anno Accademico 2016.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/g-bastianello_phd2017-03-02|
|Appare nelle tipologie:||Tesi di dottorato|