First name
Giulia
Last name
Bastianello
Year of Study
Research Center
Thesis Title
The role of ATM in the regulation of cell mechanics
Thesis Abstract
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 Ataxiatelangiectasia
genetic disorder (A-T). A-T is a rare autosomal recessive
neurodegenerative disease characterized by neurological dysfunction, multisystem
abnormalities and cancer predisposition. ATM belongs to the family of
phosphatidylinositol 3-kinase-related kinases, which also includes 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 and several proteomic screens have identified hundreds of cytoplasmic
substrates phosphorylated by ATM and ATR. Accordingly, ATM and ATR are
also 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to the nuclear envelope; moreover, recent unpublished observations in our lab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, their plasticity and their
ability to migrate across constrictions. We found that lack of ATM activity
correlates with structural alterations in the cytosol and increases cell stiffness.
Moreover, defective ATM impairs 2D locomotion and interstitial migration. ATM
is activated in cells subjected to deformation of the nucleus during the squeezing
across constrictions in 3D migration and ATM depletion impairs survival of cells
migrating inside constrictions.
12
By mass spectrometry analysis we identified a plethora of proteins involved in the
regulation of cytoskeleton and cell structure that physically 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 DNA damage response and its mutation causes the development of the Ataxiatelangiectasia
genetic disorder (A-T). A-T is a rare autosomal recessive
neurodegenerative disease characterized by neurological dysfunction, multisystem
abnormalities and cancer predisposition. ATM belongs to the family of
phosphatidylinositol 3-kinase-related kinases, which also includes 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 and several proteomic screens have identified hundreds of cytoplasmic
substrates phosphorylated by ATM and ATR. Accordingly, ATM and ATR are
also 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, their plasticity and their
ability to migrate across constrictions. We found that lack of ATM activity
correlates with structural alterations in the cytosol and increases cell stiffness.
Moreover, defective ATM impairs 2D locomotion and interstitial migration. ATM
is activated in cells subjected to deformation of the nucleus during the squeezing
across constrictions in 3D migration and ATM depletion impairs survival of cells
migrating inside constrictions.
12
By mass spectrometry analysis we identified a plethora of proteins involved in the
regulation of cytoskeleton and cell structure that physically 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.
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