Evolution is driven in part, by genetic events which result in global changes to genomic structure. Some genomic changes can be detrimental for cells / organisms. Genetic instability is a transient or a persistent state resulting from chromosomal breakage and rearrangements that causes a series of mutational events leading to gross genetic alterations, which can cause cancers and other genetic diseases. These alterations results from external and/or internal factors. External environmental factors include radiation or chemicals, which act by damaging DNA. Internal events such as oxidation and perturbation of the progression of the DNA replication by intrinsic factors such as DNA binding proteins, replication slow zones and replication fork barriers can also lead
to genetic instability.
In this study, I used the fission yeast, Schizosaccharomyces pombe as a model organism to study aspects of the regulation of eukaryote genome stability. Firstly, I set out to determine whether Translin protein, which binds to chromosome breakpoint junctions in lymphoid malignancies and sarcomas, and its partner protein Trax, have any role in causation or suppression of genetic instability. I studied the effect of removal and over expression of Trax and Translin on S. pombe with regards to growth rate, DNA damage repair and repeat instability. I find that deletion and over expression of the trax and
trans/in genes did not affect cell proliferation, morphology or DNA damage recovery. I found that Trax levels are post transcriptionally regulated by Translin, a function conserved in higher eukaryotes.
Secondly, I used two different genetic elements, RTSJ and a tRNA gene cassette (sup3-e) which generate replication fork barriers (RFBs) to study the possible role of RTSJ in the causation of genetic rearrangement. We find that the recombination potential of RFBs is not universal. We also demonstrate that intra-genomic ectopic recombination, initiated by a disruption to DNA replication, is regulated in a region-specific manrier. Lastly, we demonstrate that the trans factor Swi 1, a yeast TIMELESS homologue, differently regulate the recombination potential of replicative barriers, serving both to stimulate and suppress recombination in a barrier-specific fashion.