A telomere is the genetic segment at the end of a chromosome made up in man of (TTAGGG)n DNA repeats. Small amounts of these terminal sequences are lost in each S phase because of incomplete DNA replication although they can be replaced by telomerase reverse transcriptase (TERT) . Telomeres have key functions in:
- The mitotic clock
- Progeria (Werner's syndrome) causes accelerated telomer shortening but further the DNA helicase mutation of progeria causes impaired telomere replication and stability. However this may be secondary rather than primary. Dyskeratosis congenita is associated sometimes with a normal lifespan and is a poor model for those who associate telemore shortening and ageing.
- Stem cell differentiation - TERT activates stem cells independent of its telomere lengthening function
- Haematopoietic stem cells
- Gastrointestinal tract
- Malignant transformation
- It is over expression of TERT that allows cells in a malignancy to divide indefinitely, and the general evidence is that this occurs relatively late in the mutation sequence that lead to malignancy.
First described by American biologist Hermann Muller in 1930s.
In the 1970s, Jack Szostak noted that DNA introduced artificially into yeast began to degrade. Elizabeth Blackburn, in her studies on the unicellular protozoan Tetrahymena, noted that the end sequences of the organism's DNA ended with repeats of short DNA sequences. Working in collaboration, the two scientists found that addition of these repeated sequences to the ends of the artificial yeast DNA prevented degradation. It was not until the 1980s that Carol Gardner identified telomerase, the enzyme responsible for regeneration of the telomeres. All three shared the 2009 Nobel Prize for Medicine for their work on telomeres.
- Dyskeratosis congenita. Bone marrow failure due to mutations of the DKC1 gene. Pulmonary fibrosis in about 20%.
- Aplastic anaemia. Some forms associated with TERT and TERC mutations.
- Pulmonary fibrosis. As well as the telomerase mutations in about 15% of those with familial pulmonary fibrosis, idiopathic pulmonary fibrosis has been associated with shortened telomeres.
- Cirrhosis shortened telemeres sometimes
- Noncirrhotic portal hypertension has been associated with TERT and TERC mutations.
- TERT polymorphisms are associated with susceptibility to glioma, acute myeloid leukaemia and renal cell carcinioma.
- Ischaemic heart disease, particulary with cylomegaloviris seropositivity.
- ↑ Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood. 2008 May 1; 111(9):4446-55.(Link to article – subscription may be required.)
- ↑ Hills M, Lansdorp PM. Short telomeres resulting from heritable mutations in the telomerase reverse transcriptase gene predispose for a variety of malignancies. Annals of the New York Academy of Sciences. 2009 Sep; 1176:178-90.(Link to article – subscription may be required.)
- ↑ Spyridopoulos I, Hoffmann J, Aicher A, Brümmendorf TH, Doerr HW, Zeiher AM, Dimmeler S. Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. Circulation. 2009 Oct 6; 120(14):1364-72.(Link to article – subscription may be required.)