- Title
- DNA repair and the Fanconi Anemia pathway: insights into female meiosis and mitosis
- Creator
- Yuen, Wai Shan
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2012
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- There are numerous intrinsic and extrinsic factors that cause DNA damage. Without proper DNA repair, such damage would cause genomic instability, premature aging and cancer. The Fanconi Anemia (FA) pathway is important for the repair and resolution of interstrand crosslinks. The key events of this pathway are the ubiquitination of a FA protein, FANCD2, and its localisation onto sites of DNA damage as nuclear foci. Of interest, Gametogenetin (GGN) has been found previously to interact directly with the FA protein responsible for this ubiquitination. In this thesis, using siRNA knockdown, I examined first the role of GGN1 in HeLa cell growth and survival. The phenotypic similarities of GGN1 depleted cells and FA-deficient fibroblasts led me to investigate the role of GGN1 in the FA pathway. It was found that GGN1 was important for the localisation but not the ubiquitination of FANCD2. In addition, an automated method for FANCD2 foci quantification and analysis was developed. In comparison to mitotic cells, oocytes spend the majority of their life arrested in prophase I and this would make them vulnerable to DNA damage. This could in turn lead to female infertility and embryo abnormalities. However, there is little known about the DNA repair capacity of oocytes to respond to such damages. It was discovered, in this thesis, that oocytes have a high tolerance for interstrand crosslinks (ICLs) as compared to double stranded breaks. In combination with the expression of FA transcripts and proteins, this suggested that oocytes might have an active ICL repair. It was determined in this thesis that although oocytes had the ability to detect DNA damage, the FA pathway was found to be inactive during meiosis and only initiated upon embryo formation. The data presented in this thesis also suggest that FANCD2 might have a separate role in meiosis.
- Subject
- meiosis; mitosis; DNA repair; Fanconi Anemia; DNA damage
- Identifier
- http://hdl.handle.net/1959.13/1036684
- Identifier
- uon:13344
- Rights
- Copyright 2012 Wai Shan Yuen
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT02 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download |