Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.820379
Title: Ataxia Telangiectasia and Rad3-related protein (ATR) maintains cardiac tissue functionality
Author: Giovannetti, Irene
ISNI:       0000 0004 9355 1935
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2020
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Abstract:
To counteract DNA damage, cells have evolved several mechanisms collectively termed as the DNA damage response (DDR). A key member of DDR signaling in mammalian cells is ATR (Ataxia Telangiectasia and Rad3-related protein), a PIKK kinase that is activated by single-strand DNA lesions in response to replication stress. Severe ATR deficiency owing to hypomorphic germline mutations in ATR causes the Seckel syndrome, a neurodevelopmental and premature aging disorder. Besides its role in the DDR, ATR is activated by a variety of stimuli, including topological, osmotic and mechanical stress and contributes in the maintenance of proper nuclear integrity and membrane tension. Notably, ATR-defective cells exhibit intrinsic nuclear softness and fragility, raising the possibility that cells and tissues constantly undergoing mechanical strain, such as the heart muscle, might be particularly affected by ATR loss. To address this point, we analyzed cardiac muscle tissue from a mouse model of the human ATR Seckel syndrome (ATRS). By functional echocardiography and immunohistochemistry analysis, we showed that ATR Seckel cardiac tissue presents major morphological defects, particularly affecting cardiomyocytes’ nuclei, accompanied by a reduced cardiac functionality. Accumulation of nuclear and DNA damage due to lack of ATR contributes to the mis-localization of cardiomyocyte self-DNA from the nucleus to the cytoplasm and to the consequent activation of inflammatory processes through the STING pathway. In the current study, we show that lack of ATR strongly impacts cardiac tissue structure and function and contributes to development of cardiac inflammation; the insights gained from understanding the interplay between ATR signaling, DNA damage response and inflammation will help in the diagnosis of cardiac diseases in Seckel Syndrome and in the development of therapies to improve one of the pathological consequences of this disorder.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.820379  DOI:
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