Translin and Trax are highly conserved, paralogous proteins that are functionally associated with one another. They have been shown to participate in a wide range of biological pathways, including tRNA processing, mRNA regulation in neuronal cells, spermatogenesis function and pre-microRNA degradation during oncogenesis, a role which has given rise to the notion that they could represent a suitable pharmaceutical target for several forms of neoplasia. Translin was originally identified as a cancer-associated, chromosomal breakpoint junction binding protein, which led to the proposal that it functions in the DNA damage response. The aim of this study was to build on previous, unpublished work to further establish how Translin and/or Trax contribute to the maintenance of genomic integrity. Given the conserved nature of the two proteins, their function was investigated using the facile and genetically tractable experimental model, Schizosaccharomyces pombe. Preliminary data resulted in the hypothesis that S. pombe Translin (Tsn1), but not Trax (Tfx1), is involved in processing genomic RNA:DNA hybrids and could be functionally linked to RNase H activity for genome maintenance control. Here we reveal a functional association between Tsn1 and the RNase H Rnh201, but attribute this to non-RNase H activity of Rnh201, and, counter to our original hypothesis, find no evidence for a role for Tsn1 in RNA:DNA hybrid processing for genome stability maintenance, suggesting a distinct functional pathway. This is extended by exploring the relationship between Tsn1 and Tfx1 with the RNA:DNA helicase, Sen1. Whilst we find no functional relationship between Tsn1 and Sen1, we do reveal a possible functional redundancy between Sen1 and Tfx1, which opens a new avenue of investigation. Previous work has also demonstrated functional redundancy between Tsn1 and the RNA interference-associated RNAse III, Dcr1, which functions in an RNAi-independent fashion to maintain genome stability by displacing RNA polymerase II form the genomic template to avoid genome destabilisation caused by transcription-replication conflicts. Here, we extend this to reveal a complex functional relationship between Dcr1, Tsn1 and Rnh201 and provide a model that proposes an auxiliary role for Tsn1 for displacing RNA polymerase II from genomic DNA to prevent replication- associated genome instability. Finally, we clone the human TSN (Translin) gene and demonstrate that it can replace S. pombe tsn1 encoded function(s) for genome maintenance, and it can do this in the absence of human TSNAX. We also demonstrate that this is not dependent on the RNase activity of human TSN. This not only demonstrates the conservation of this function within the Translin family, but also offers a simple system in which to study this important human oncogene and therapeutic target.