The Role of RAD50 in protecting the genome

Sa ariwijaya, Mohd Shazrul Fazry (2013). The Role of RAD50 in protecting the genome PhD Thesis, School of Medicine, The University of Queensland.

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Author Sa ariwijaya, Mohd Shazrul Fazry
Thesis Title The Role of RAD50 in protecting the genome
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2013
Thesis type PhD Thesis
Supervisor Martin F. Lavin
Magtouf Gatei
Total pages 233
Total colour pages 65
Total black and white pages 168
Language eng
Subjects 060199 Biochemistry and Cell Biology not elsewhere classified
060402 Cell and Nuclear Division
060407 Genome Structure and Regulation
Abstract/Summary The MRE11-RAD50-NBN complex plays a crucial role in coordinating DNA double strand breaks response. Studies of NBN and MRE11 deficiencies in the human cell models (derived from Nijmegen Breakage Syndrome (NBS) and Ataxia-telangiectasia like disorder (ATLD) patients, respectively) have been extensively investigated compared to RAD50 deficiency (Nijmegen Breakage Syndrome like disorder (NBSLD)). This is because, to date only two patients have been identified with NBSLD and only one has been characterised. In this study, fibroblasts from this NBSLD patient were further characterised to identify new possible roles of RAD50 in protecting the genome. It is demonstrated that the RAD50 S635 phosphorylation site plays a role in mediating the intra-S checkpoint after IR, and it is hypothesised to play a role as an ATM adaptor to regulate downstream ATM signalling. RAD50 interactors, such as, RPA1, RPA2, ATRIP, FancD2, DNA-PK, 53BP1, MRE11, NBN, TRF2, RAP1, and MDC1 are found to be downregulated in RAD50 deficient cells. RAD50 interacts with STAT6, a transcription factor, which is hypothesised to regulate the expression of these proteins. This was further supported by localisation of STAT6 in RAD50 deficient cell nuclei compared to control nuclei. It was suggested that STAT6 in RAD50 deficient cells bind to the genes coding for these proteins and inhibit their transcription. A novel role of RAD50 in mitosis has been identified. RAD50 localised to the kinetochore during prophase to metaphase, and moved to the midzone in anaphase. During telophase, RAD50 became fully localised to the cells midbody to assist cytokinesis. RAD50 deficient cells were shown to suffer from abnormal chromosomes segregation, centrosome abnormality, and cytokinesis failure due to failure to phosphorylate Aurora kinase B (AuB). AuB was also shown to interact directly to RAD50. Two other kinetochore proteins were also shown to interact directly with RAD50, they are Bub1 and ZW10. Here it is suggested that RAD50 plays a role in regulating chromosome segregation and cytokinesis signalling during mitosis.
Keyword Nijmegen Breakage Syndrome like disorder
mitotic defect
Intra-S checkpoint
spindle checkpoint
abnormal nuclei

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Created: Mon, 23 Dec 2013, 13:07:21 EST by Mohd Shazrul Sa Ariwijaya on behalf of Scholarly Communication and Digitisation Service