Supervisors:
Dr Takashi Kubota - The Institute of Medical Sciences, University of Aberdeen - [Email Address Removed]
Professor Tom Owen-Hughes - School of Life Sciences, Centre for Gene Regulation and Expression, University of Dundee - [Email Address Removed]
Chromatin organisation is critical for gene transcription, DNA replication and DNA repair, and derailed chromatin organisation is linked to cancers (Narlikar et al. 2013 Cell). ATP-dependent chromatin remodelling complexes including SWI/SNF regulate chromatin structure, altering accessibility of specific DNA regions, including DNA damage sites. Although chromatin remodelling is important for DNA repair, how SWI/SNF regulates DNA repair through a checkpoint kinase is not well understood. Based on our unpublished data and other reports (Zhang et al. 2013 Front Oncol; Kapoor et al. 2105 Genes Dev), we hypothesise that SWI/SNF directly interacts with the Mec1 checkpoint kinase (ATR in human) to regulate a checkpoint pathway, a surveillance mechanism to maintain genome integrity, as well as remodelling chromatin at DNA damage sites.
We recently purified the SWI/SNF-Mec1 complex successfully as a strongly bound complex (Nikolov et al. provisionally accepted in Nature Communications) dependent on conditions used, suggesting specific requirement(s) for their binding.
Aim
The aim of this project is to reveal how the SWI/SNF-Mec1 (ATR) complex is formed and acts in DNA repair in yeast and human. To this end, the project will address two central questions:
A. How does yeast SWI/SNF interact with Mec1 and activate it?
Using molecular biology techniques (e.g., genetics, proteomics, ChIP, and Next Generation Sequencing), the student will investigate how yeast SWI/SNF interacts with Mec1, and also where and when. The student will further investigate how SWI/SNF mediates DNA repair via Mec1, e.g., whether SWI/SNF activates Mec1 kinase activity at specific sites and whether Mec1 modulates SWI/SNF’s chromatin remodelling activity.
B. Does human SWI/SNF interacts with ATR and activate it?
The student will test the interaction of human SWI/SNF with ATR (human Mec1) in a series of different conditions based on our method for yeast and the findings in Part A. The student will further investigate whether SWI/SNF mediates DNA repair through interacting with ATR using genetic and proteomic approaches in human cell lines.
Overall, this research will elucidate new function of SWI/SNF in DNA repair and provide major new insight into the mechanisms ensuring genome integrity.
The student will work primarily in the Kubota lab (University of Aberdeen), expert in DNA replication and repair, and the internationally recognised Owen-Hughes group (University of Dundee) who contribute expertise in the chromatin remodellers.
Application Procedure:
Please visit this page for full application information: http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO application form, along with academic transcripts to Alison Innes at [Email Address Removed]
Two references should be provided by the deadline using the EASTBIO reference form.
Please advise your referees to return the reference form to [Email Address Removed]
Unfortunately due to workload constraints, we cannot consider incomplete applications
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