Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626775
Title: The role of ATMIN in regulating ATM signalling
Author: Zhang, T.
ISNI:       0000 0004 5363 5624
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Abstract:
Ataxia telangiectasia-mutated (ATM), the protein kinase that is mutated in patients with ataxia telangiectasia (A-T), is a central player in the cellular response to DNA damage. ATM is activated following double-strand breaks by MRE11-RAD50-NBS1 complex (MRN), which acts as an initial sensor of DSB. ATM is also activated by stimuli that change chromatin structure such as chloroquine and hypotonic shock, which depends on the ATM-interactor protein (ATMIN) as a cofactor. In this study, I show that there exists competition between ATMIN and NBS1 for ATM binding and this can regulate ATM signalling. The absence of one cofactor can lead to enhanced signalling through the alternative pathway. Furthermore, I also characterise the role of an E3 ligase that regulate the interaction between ATMIN and ATM by mediating ATMIN mono-ubiquitination. Thus ATMIN ubiquitination could be an important step in ensuring robust ATM activation after IR. In addition, I also show that ATMIN is required for ATM signalling after replication stress to protect against genomic instability in the form of anaphase bridges and aberrant chromosome segregations. ATM is activated by replication stress and is required for the formation of 53BP1-containing nuclear bodies, which protect fragile sites. ATMIN interacts with WRNIP and RAD18 in a complex that is required to activate ATM at sites of stalled replication forks. Furthermore, using a genome-wide screening approach, I identified additional factors that regulate ATM signalling after replication stress. The 8-oxo-guanosine repair pathway could represent a link between ATM signalling and genomic instability. I show that the components of base excision repair pathway are required for the activation of ATM and formation of 53BP1 nuclear bodies that protect fragile sites in the maintenance of genome stability.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.626775  DOI: Not available
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