eprintid: 1418933
rev_number: 43
eprint_status: archive
userid: 608
dir: disk0/01/41/89/33
datestamp: 2014-06-12 07:56:18
lastmod: 2019-10-19 08:10:01
status_changed: 2014-06-12 07:56:18
type: thesis
metadata_visibility: show
item_issues_count: 0
creators_name: Zhang, T
title: The role of ATMIN in regulating ATM signalling
ispublished: unpub
divisions: A01
divisions: B02
divisions: C08
keywords: ATM, ATMIN, DNA damage
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.
date: 2014-03-28
vfaculties: VFLS
oa_status: green
full_text_type: other
thesis_class: doctoral_open
language: eng
thesis_view: UCL_Thesis
primo: open
primo_central: open_green
verified: verified_manual
elements_source: Manually entered
elements_id: 926430
language_elements: EN
lyricists_name: Zhang, Tianyi
lyricists_id: TZHAN64
full_text_status: public
pagerange: 1 - 215
pages: 215
institution: UCL (University College London)
department: Cancer Research UK- London Research Institute
thesis_type: Doctoral
citation:        Zhang, T;      (2014)    The role of ATMIN in regulating ATM signalling.                   Doctoral thesis , UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1418933/1/Thesis%20revised%20version%20formatted.pdf