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Title: The function of SPO11 in human cancer cells
Author: Alahdal, Maryam Abdulrahman
ISNI:       0000 0004 7229 5848
Awarding Body: Prifysgol Bangor University
Current Institution: Bangor University
Date of Award: 2017
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Cancer is currently the second most common disease resulting in high death rates globally ( accurate to 2015). A combination of various genetic and/or epigenetic modifications, which lead to distinct chromosomal abnormalities and/or mutations, cause somatic cell transformations leading to the formation of cancer cells. New strategy is emerging with the relatively recent identification and functional characterisation of cancer testis antigens (CTAs), which are antigens, encode by gene with expression normally restricted to the testis of adult males, which become activated in cancers. These (CTAs) can potentially serve as cancer-specific biomarkers, and could play a core role in cancer diagnosis and subsequent prognosis. This current study focuses on the human CTA gene, SPO11 and the expression, protein localisation and function of this CTA in different cancer cells. In mice, infertility is observed when SPO11 is dysfunctional. Similarly, the homozygous null mutation of Spo11 contributes to the arrest of meiotic division mid-prophase I. In several model organisms, including S. pombe, Drosophila, Caenorhabditis elegans and Coprinus cinereus, the loss of Spo11 function results in the production of defective gametes, ultimately indicating the failure of the meiotic process. Thus, Spo11 protein is necessary for accurate gamete formation. During this study SPO11 has been detected in testis, most cancer cells, but not found in the healthy normal tissues. SPO11 knockdown in different cancer cell lines results in reduced proliferation of these cells in an apoptosis-independent manner. SPO11 was also shown to co-localise with Bloom protein, a recQ-like-helicase involved in decatenation of dividing chromosomes. These results taken together suggest that the presence of SPO11 in non-meiotic cells changes the dynamics/timing of the cell cycle potentially by interfering with or modulating the chromosome structure during cell division. Instability within the chromosome structure and cell proliferation are two major factors considered to be involved in the development of human cancer. This study propose that the SPO11 gene could be playing a critical role in controlling the genome stability of cancer cells, and thus necessary for stimulating and maintaining the oncogenic processes. SPO11 when present in cancer cells may also lead to aberrant initiation of DNA double-stranded breaks and/or altered DNA replication/chromosome segregation during mitosis resulting in chromosome changes. Future work was done in this study to purify SPO11 expressed in E. coli for use in crystal structure and in vitro assays to develop drugs to specifically target this protein in cancers where it has been detected.
Supervisor: Mcfarlane, Ramsay ; Wakeman, Jane Sponsor: Ummulqura University
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available