|Title:||Mechanisms of somatic hyper-mutation|
|Authors:||Lau, Kun Kan Edwin|
|Publisher:||University of Sydney.|
Centenary Institute of Cancer Medicine and Cell Biology.
Central Clinical School RPAH
|Abstract:||My study aims at determining if DNA-PKcs, a NHEJ factor, and REC8, a cohesin that facilitates HDR, contribute to SHM. Although my data do not support their participation in SHM in mouse B cells, I discovered that Rec8-/- mice had slightly lower red cell and platelet counts. Moreover, Rec8-/- bone marrow cells competed poorly when put into competition with Rec8+/+ bone marrow cells, and this defect can be traced to the earliest haematopoietic progenitors. I also discovered that Rec8-/- mice carry an unexpected one base-pair deletion in the adjacent Ipo4 gene, resulting in undetectable IPO4 protein level in Rec8-/- MEFs. Since REC8 is a meiotic protein with no established function in mitotic cells, the above mentioned defects are probably due to IPO4 deficiency. Next part of my study was to test whether SMUG1 participates in antibody mutation. Di Noia et al. (2006) showed that SMUG1 transgenic over-expression reduced SHM. My study is to confirm this observation using retroviral transduction, with UNG2 as a control. My results suggest that over-expression of either ecotopic SMUG1 or UNG2 enhances faithful BER, with only subtly different SHM phenotypes. Therefore I concluded that the previously proposed higher fidelity of SMUG1-mediated uracil repair relative to UNG2-mediated uracil repair has been over-stated.|
|Access Level:||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|LAU Kun Kan Edwin - Final thesis.pdf||4.36 MB||Adobe PDF|
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