Human translin is a conserved protein, unique in its ability to bind both RNA and DNA. Interestingly, GTP binding has been implicated as a regulator of RNA/DNA binding function of mouse translin (TB-RBP). We cloned and overexpressed the translin orthologue from Drosophila melanogaster and compared its DNA/RNA binding properties in relation to GTP effects with that of human protein. Human translin exhibits a stable octameric state and binds ssDNA/RNA/dsDNA targets, all of which get attenuated when GTP is added. Conversely, Drosophila translin exhibits a stable dimeric state that assembles into a suboctameric (tetramer/hexamer) form and fails to bind ssDNA and RNA targets. Interestingly enough, CD spectral analyses, partial protease digestion profile revealed GTP-specific conformational changes in human translin, whereas the same were largely missing in Drosophila protein. Isothermal calorimetry delineated specific heat changes associated with GTP binding in human translin, which invoked subunit "loosening" in its octamers; the same effect was absent in Drosophila protein. We propose that GTP acts as a specific molecular "switch" that modulates the nucleic acid binding function selectively in human translin, perhaps by affecting its octameric configuration.