Structural studies of two proteins involved in the maintenance of genomic stability FEN 1 and DNA-PKcs
dc.contributor.advisor
Spagnolo, Laura
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dc.contributor.advisor
Walkinshaw, Malcolm
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dc.contributor.author
Parker, James M.
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dc.contributor.sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
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dc.date.accessioned
2017-04-26T14:31:13Z
dc.date.available
2017-04-26T14:31:13Z
dc.date.issued
2016-06-28
dc.description.abstract
Genomic stability refers to an organism’s ability to maintain and pass forward its
genetic information. There are a raft of proteins and pathways whose sole purpose is
maintaining this stability through swiftly replicating DNA as well as accurately repairing
damage caused through contact with endogenous and exogenous DNA damaging elements.
This study will focus on the structural aspects of two proteins that play a part in different
areas of genome maintenance.
Flap Endonuclease 1 (FEN 1) works in DNA replication, where it is tasked with
removing a small RNA flap that is created during Okazaki fragment formation. This flap
removal is essential to mature these fragments into one continuous strand of nascent DNA.
Using the archeon Pyrococcus abyssi (Pab) as a model system has the advantage of possessing
simple replicative machinery, whilst bearing striking similarities with the human system. Pab
is a hyperthermophilic, piezophile meaning it thrives in conditions of high temperature and
pressure.
DNA-dependent protein kinase (DNA-PK) is a holoenzyme that plays a role in the
Non Homologous End Joining (NHEJ) pathway by repairing DNA double strand breaks
(DSB’s). In cancer therapy, a patient is exposed to DNA damaging elements, leading to an
ever-increasing population of DSBs. If an inhibitor of DNA-PKcs were introduced along
with this therapy it could potentiate its effect, as the cancerous cells will be less able to repair
the damage. The aim of this part of the study is to determine a protocol to generate pure,
soluble, correctly folded protein for the purposes of biophysical characterisation and X-ray
crystallographic structural studies.
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dc.identifier.uri
http://hdl.handle.net/1842/21709
dc.language.iso
en
dc.publisher
The University of Edinburgh
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dc.subject
cellular repair pathways
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dc.subject
DNA-PK
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dc.subject
FEN 1
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dc.subject
genome maintenance
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dc.subject
protein
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dc.title
Structural studies of two proteins involved in the maintenance of genomic stability FEN 1 and DNA-PKcs
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dc.type
Thesis or Dissertation
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dc.type.qualificationlevel
Doctoral
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dc.type.qualificationname
PhD Doctor of Philosophy
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