Sci. Aging Knowl. Environ., 26 February 2003
Vol. 2003, Issue 8, p. tg2
GENETICALLY ALTERED MICE
Telomerase RNA Component (Terc) Knockout Mice
||Telomerase RNA component (Terc) knockout mice (Terc-/-; also called mTerc-/-, mTER-/-, mTR-/-)
||60% C57BL6; 37.5% 129Sv; 2.5% SJL
||mTerc (mouse telomerase RNA component)
|Type of change
|Nature of protein
||Telomerase is composed of a protein (the catalytic subunit) and a piece of RNA. The RNA, called telomerase RNA candidate 3 (TRC3), serves as a template for the addition of telomeric repeat sequences. A 451-nucleotide gene (mTerc or Trc3) encodes the telomerase RNA component, and TRC3 co-purifies with telomerase activity. As expected, TRC3 is highly expressed in tumor cells and in the germ line, two places where high telomerase activity is present. In HeLa cells transfected with antisense TRC3, telomeric DNA is lost and cells die after 23 to 26 divisions. Thus, telomerase is required for long-term proliferation of tumor cells in culture.
||Terc-/- mice lack detectable telomerase activity and are viable for the six generations analyzed. Early generations of mTerc-/- mice show little change in telomere length and no premature aging phenotypes. But in subsequent generations (5 to 6), the telomeres shrink and mice show a number of premature aging phenotypes, including gray hair, increased incidence of spontaneous malignancies, and decreased life-span.
Telomerase-deficient cells could be immortalized in culture and transformed by viral oncogenes, and could generate tumors in nude mice after transformation. It was shown that telomeres shortened at a rate of 4.8 ± 2.4 kb per Terc-/- generation. Cells from the fourth Terc-/- generation onward possessed chromosome ends lacking detectable telomere repeats and showed aneuploidy and chromosomal abnormalities, including end-to-end fusions. Taken together, these results reveal that telomerase is essential for telomere length maintenance, but is not required for the establishment of cell lines, oncogenic transformation, or tumor formation in mice.
|Corresponding human phenotype
||Dyskeratosis congenita, autosomal dominant [Terc, 821-base pair deletion]: The Online Mendelian Inheritance in Man (OMIM) number for the autosomal dominant form of dyskeratosis congenita is 127550. In a large family with autosomal dominant dyskeratosis congenita, Vulliamy et al. (2001) identified an 821-base pair deletion on chromosome 3q that removes the 3' 74 base pairs of Terc.
Aplastic anemia [Terc, C-to-G transition at nucleotide 72]: The OMIM number for aplastic anemia related to Terc is 602322.
Vulliamy et al. (2002) found a C-to-G transversion in nucleotide 72 of the Terc gene in a 33-year-old man with nonsevere aplastic anemia and severe osteoporosis.
||M. A. Blasco, H. W. Lee, M. P. Hande, E. Samper, P. M. Lansdorp, R. A. DePinho, C. W. Greider, Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25-34 (1997).
H. W. Lee, M. A. Blasco, G. J. Gottlieb, J. W. Horner 2nd, C. W. Greider, R. A. DePinho, Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569-574 (1998).
H. Niida, T. Matsumoto, H. Satoh, M. Shiwa, Y. Tokutake, Y. Furuichi, Y. Shinkai, Severe growth defect in mouse cells lacking the telomerase RNA component. Nat. Genet. 19, 203-206 (1998).
||Mouse Genome Informatics: http://www.informatics.jax.org/javawi/servlet/Marker?key=31865
Also see below.
||Terc-/- mice are commercially available through the Jackson Laboratory (stock no. 004132) (http://jaxmice.jax.org/).
||SAGE KE's Genes/Interventions database:
The Genome Database entry for Terc:
National Center for Biotechnology Information LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7012
OMIM entries for autosomal dominant dyskeratosis congenita: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602322
OMIM entries for aplastic anemia: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602322
||Terc, telomerase, telomerase RNA, telomere, TRC3
February 26, 2003
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- T. Vulliamy, A. Marrone, I. Dokal, P. J. Mason, Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359, 2168-2170 (2002). [CrossRef][Medline]
- A. I. Soder, S. F. Hoare, S. Muire, A. Balmain, E. K. Parkinson, W. N. Keith, Mapping of the gene for the mouse telomerase RNA component, Terc, to chromosome 3 by fluorescence in situ hybridization and mouse chromosome painting. Genomics 41, 293-294 (1997).[CrossRef][Medline]
Telomerase RNA Component (Terc) Knockout Mice. Science's SAGE KE
(26 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/tg2