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Faculty

Manor Haim, Professor Emeritus

Phone:  (972)-4-8293456

Research area 2

Research area 2: Use of fission yeast for deciphering the biological functions of the proteins Translin and TRAX.

The human protein Translin is an octamer consisting of eight identical subunits of 228 amino acids. It was highly conserved in evolution- the mouse, chicken, Xenopus and Drosophila Translins are 99%, 92%, 88% and 68% homologous to the human Translin. A Translin homologue also exists in the fission yeast S. pombe (54% homology to the human protein), but not in the budding yeast S. cerevisiae. TRAX is a protein that was identified by virtue of its association with Translin and has also been conserved in evolution. We have shown that the Translin octamer specifically binds the d(GT)n strand of the highly dispersed DNA microsatellite repeats d(GT)n.d(AC)n, and the G-strand telomeric repeats d(TTAGGG)n. Other laboratories reported that Translin binds (with much lower affinities) single-stranded DNA molecules consisting of sequences flanking chromosomal translocations in leukemia and lymphoma cells. Thus, Translin might play a role in the metabolism of microsatellite DNA sequences and telomeres and might be also involved in chromosome translocations. 

However, Translin was also reported to bind specific RNA sequences in mRNAs. Based on those findings, it has been suggested that Translin plays a role in the control of mRNA translation and transport. One recent finding was that Translin is required for transport of mRNA encoding the brain-derived neurotrophic factor (BDNF) from nerve cell soma to the ends of dendrites that are situated in close proximity to the synapses. Such transport allows synthesis of BDNF in response to certain signals and its rapid delivery into the synapses, thereby affecting synaptic plasticity. Other studies have indicated that a Translin-Trax octameric complex plays an important role in RNAi metabolism in Drosophila melanogaster.

Thus, Translin appears to be a multifunctional protein. To better understand the molecular basis for Translin functions, we have undertaken a study of the Translin and TRAX homologues in S. pombe cells. This organism provides us with the ability to use for such studies sophisticated genetic manipulations, as well as biochemical techniques. Moreover, we consider it likely that the information gained in the yeast cells would be helpful for a further analysis of the human proteins. Our initial characterization of the S. pombe Translin and TRAX has been described in an article listed below in our selected publications. In another more recent article, which is also listed below, we presented, for the first time, a systematic mapping of nucleic acids and protein-binding surfaces on the 3D-structure of Translin. The strength of these data stems from our combined use of powerful bioinformatics computation tools and molecular genetics techniques. 

In addition to our recent structural studies of Translin, we are engaged in a project designed to identify proteins that form specific complexes with spTranslin and spTRAX in S. pombe cells. In this ongoing project, we have identified several such proteins and are presently engaged in attempts to further characterize these complexes.

Fig. 2: Interaction surfaces for single-stranded RNA and DNA on the S. pombe (left) and the human (right) Translin monomer structures

These RNA and DNAinteraction surfaces include polar and positively charged amino acids, mostly arginines, surrounding a shallow cavity. Residues are colored according to the hydrophobicity scale of Kyte and Doolittle (Kyte,J. and Doolittle,R.F. (1982), J. Mol. Biol. 157, 105-132), from brown (most hydrophilic residues) to green (most hydrophobic residues). The shallow cavities in both cases are surrounded by a blue line. Arginine residues, which have the highest hydrophilic score, are shown in red. This drawing was taken from our recent NAR paper (Eliahoo,E., Ben,Y.R., Perez-Cano,L., Fernandez-Recio,J., Glaser,F., and Manor,H. (2010),  Nucleic Acids Res. 38, 2975-2989).

References

1. Aharoni,A., Baran,N., and Manor,H. (1993), Nucleic Acids Res. 21, 5221-5228.

2. Han,J.R., Gu,W., and Hecht,N.B. (1995), Biol. Reprod. 53, 707-717.

3. Aoki,K., Suzuki,K., Sugano,T., Tasaka,T., Nakahara,K., Kuge,O., Omori,A., and Kasai,M. (1995), Nat. Genet. 10, 167-174.

4. Chiaruttini,C., Vicario,A., Li,Z., Baj,G., Braiuca,P., Wu,Y., Lee,F.S., Gardossi,L., Baraban,J.M., and Tongiorgi,E. (2009), Proc. Natl. Acad. Sci. U. S. A 106, 16481-16486.

5. Liu,Y., Ye,X., Jiang,F., Liang,C., Chen,D., Peng,J., Kinch,L.N., Grishin,N.V., and Liu,Q. (2009), Science 325, 750-753.