Genetic analyses of XLF and KU and their functional impacts on DNA-double strand break repair in human cells

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http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/59105 http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/59105 http://eprints.org/relation/isIndexCodesVersionOf http://etheses.bham.ac.uk/id/document/59105 archive 4031 disk0/00/00/31/10 2012-01-11 14:38:02 2022-12-31 03:40:03 2012-01-11 14:38:02 thesis show 0 Al-Emam Ahmed Mohamed Ahmed 0000-0002-5415-8992 Kysela Boris University of Birmingham Genetic analyses of XLF and KU and their functional impacts on DNA-double strand break repair in human cells unpub RB 10col_mede Author requested extension to 31/12/2017 (GL 12/01/2015) Access restriction has been extended 5-6 times since the author graduated. The work has now been inaccessible for close to 8 years and the author has refused or ignored user requests to view the work. Author has been informed that the access restriction will not be extended again, any further requests to extend will be declined (RA 12/12/2019) Publication delays due to covid - extended restriction until 31/12/2021. (AH 25/11/2020) Authors ORCID number 0000-0002-5415-8992 added (AH 26/11/2020) Author contacted us 07/12/2021 requesting extension to 31/12/2022 - record updated (AH 09/12/2021). Email saved in folder (AH 09/02/2022) Author requested a further extension - request made for evidence that publication is still ongoing, awaiting author response (RA 09/12/2022) XRCC4-like factor (XLF) is the most recently discovered core member of the nonhomologous end joining (NHEJ) machinery. XLF enhances ligation of DNA ends by DNA ligase IV (LIG4) and functionally interacts with KU70. Previous results showed that some polymorphic changes in LIG4 impact on the efficiency of double strand breaks (DSBs) repair. A random Caucasian population sample was screened for XLF polymorphic mutations with similar functional impact. This analysis identified two novel noncoding single nucleotide polymorphisms (SNPs). To address the regulation of XLF and KU70, the acetylation status of both proteins were analysed. It has been found that XLF undergoes acetylation both in vitro and in vivo and the acetylation sites were mapped in vitro by mass spectrometry. Preliminary analysis has indicated that XLF deacetylation might be histone-deacetylase (HDAC3) dependent. For KU70, it has been found that lysine residues K317, K331 and K338 are critical for NHEJ. Cells overexpressing aceto-mimicking or aceto-blocking mutants of these residues are radiosensitive and defective in DSBs repair (DSBR). This indicates that the dynamic regulation of the acetylation/deacetylation status of these residues is critical for DSBR in response to ionizing radiation. These findings establish the importance of non-histone repair protein acetylation in the regulation of NHEJ and define new possible therapeutic targets for cancer treatment. 2011-12 2011-10 graduation eng 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. restricted 2022-12-31 amaemam@mans.edu.eg or alemam.ahmed@gmail.com ubira@lists.bham.ac.uk public 227 University of Birmingham School of Clinicial and Experimental Medicine d_ph na 2011-12 graduation