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THE COUNCIL FOR TOBACCO RESEARCH-U.-S.A., INC. 900 THIRD AVENUE NEW YORK. N.Y. 10022 Memorandum To: Dr. H. McAllister and Staff Fran: D.H.Ford Re: Site visit with Dr. Carol Greider, Cold Spring Harbor, NY, July 28, 1994. Grant No.3370R2 entitled "Telomerase in cellular immortalization." Goal: To determine the role of telomerase in immortalized cells. In a recent review publication which ACKs CTR, Dr. Greider describes the numerous roles which telaneres appear to play within mammalian and other eukaryotic cells. These include chrcmosane length maintenance, chranoscYne stability, transcriptional silencing, chrcHno- some positioning in the nucleus and healing, generation of artificial chranosanes, cellular senescence and cancer. Dr. Greider's current investigations are directed toward under-:, standing the role of telomerase and telanere-binding proteins in cellular senescence and cancer. Since telomerase maintains the repeated nucleotide sequence of d(TTAGGG) at the ends of chrcmosomes and is-present in a number of types of cancer, but absent in non-dividing sanatic cells, various approaches have been undertaken to inhibit this enzyme. One approach Dr. Grieder had considered was to canpetitively inhibit the telomerase in cultured mammalian ce l ls by gr owing them in the presence of high concentrations of the oligonucleotide. However, Dr. Shay's group at the Un. of Texas has attempted this procedure. and found it to be ineffective.in Pducing telanere shortening. Thus, she is focusing her efforts on attempting to inhibit telanerase using antisense oligonucleotides directed against the RNA compcnent. She has cloned mouse telomerase RNA. which is currently being purified by. Dr. Maria Blasco, who joined Dx. Greider in June, 1993 , using a procedure similar to that previously used by Dr. Greider to clone and purify the Tetrahymena telomerase RNA c omp alent . Interestingly, there appears to no telomerase in the intestinal epithelium. However, this may have been an artifactual observation duet,°a dilution of the enzyme by the presence of ncxi-dividing cells at the apices of the intestinal crypts and the presence of some underlying parenchymal tissue. She plans to repeat this after isolating the cells from the crypts. Not so surprising, there was no telanerase in brain tissue. However, since it was essentially a sample of cortex which was examined in which there are essentially no dividing cells, this was to be expected. She may attempt another evaluation of brain tissue, using the external granule cell layer of the cerebellum wherein thlW is a considerable amount of cel.l replicatbon. This is an interesting study of considerable interest currently in many laboratories, because of the many roles telaneres appear to have in regulating chranosomal function.and esxpression. Dr. Greider appears to be making excellent progress in what appears to be an investigation of considerable relevance to cancer., and in senescence. DHF