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The role of linker histone variant in double strand break repair

Arbon, Darren D (2010)
Ph.D. thesis, University of Birmingham.

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Eukaryotic DNA is packaged into chromatin, providing a physical and structural barrier for regulatory and effector proteins to access the DNA. It has been shown that linker histone variants inhibit the double strand break (DSB) repair pathway known as non-homologous end joining (NHEJ). NHEJ, in vivo, requires the KU complex, the DNA dependent protein kinase (DNA-PK) and the DNA ligase IV/XRCC4 (LX) complex. In vitro analysis has shown that several linker histone variants are all phosphorylated by DNA-PK. Depletion of a specific linker histone variant protein levels by short interfering RNA renders cells radiosensitive and increases the levels of un-repaired DSBs following exposure to ionising radiation. This linker histone variant interacts with both DNA ligase IV and XRCC4 in vivo, along with DNA-PK, the KU complex and nucleolin. Interestingly, the interaction with nucleolin only occurs in the presence of DNA damage following exposure to ionising radiation. In vitro analysis has shown that this linker histone variant is able to form stable complexes in the presence of DNA and the LX complex, and very efficiently stimulate LX-mediated ligation of double stranded DNA. These findings establish a role for a linker histone variant in the NHEJ pathway.

Type of Work:Ph.D. thesis.
Supervisor(s):Kysela, Boris and Maher, Eamon R
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Medical & Molecular Genetics
Subjects:R Medicine (General)
Institution:University of Birmingham
ID Code:1129
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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