Zhang, T;
(2014)
The role of ATMIN in regulating ATM signalling.
Doctoral thesis , UCL (University College London).
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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.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The role of ATMIN in regulating ATM signalling |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Keywords: | ATM, ATMIN, DNA damage |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1418933 |
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