Telomeres and human disease

Authors

  • Predrag Slijepčević Brunel Institute of Cancer Genetics and Pharmacogenomics, Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex

Keywords:

Genetic diseases, Telomeres, DNA sequences, Premature ageing.

Abstract

Telomeres are specialized structures at chromosome endsrequired for chromosome stability maintenance. They consistof a specific repetitive DNA sequence and a set of associatedproteins that form a protective structure at chromosomeends. The enzyme telomerase, which is active in stemcells but not in normal somatic cells, synthesizes telomericDNA sequence. This enzyme is important for cell proliferativepotential and most cancer cells have active telomerase.Telomeres are shorter in older individuals than in younger individualsand they may be viewed as a “biological clock”. Theevidence is accumulating that telomere maintenance plays asignificant role in the pathology associated with some humandiseases. There are several human genetic diseases that showaccelerated shortening of telomeric DNA sequences includingDyskeratosis congenita, Fanconi anemia, ataxia telangiectasia,Nijmegen breakage syndrome, Werner syndrome,Bloom syndrome, pulmonary fibrosis and ataxia telangiectasialike disease. A common feature of these diseases is acceleratedtelomere shortening due to increased cell turnoverthat eventually leads to signs of premature ageing. Commondiseases lacking an apparent genetic component such as atherosclerosis,heart failure, liver cirrhosis and ulcerative colitis,also show accelerated telomere shortening in affected tissues,that eventually causes tissue specific pathology. Factors thatincrease cell turnover may be detected by measuring telomerelength in the human population and so far several such factorshave been identified including: smoking, obesity and exposureto psychological stress. It is likely that future researchwill reveal an even more extensive role of defective telomeremaintenance in human disease and conditions that elevatedisease risk.

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Author Biography

Predrag Slijepčević, Brunel Institute of Cancer Genetics and Pharmacogenomics, Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex

References

McClintock B. The stability of broken ends of chromosomes of Zea mays. Genetics. 1941; 23: 234-82.

Muller HJ. The remaking of chromosomes. Collecting Net. 1938; 13: 181-95.

Blackburn E, Gall J. A randomly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol. 1978; 120: 33-53.

Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. PNAS USA. 1988; 85: 6622-6.

Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985; 43: 405-13.

Harley CB. Telomerase is not an oncogene. Oncogene. 2002; 21: 494-502.

Ducrest A-L, Szutorisz H, Lingner J, Nabholz M. Regulation of human telomerase reverse transcriptase. Oncogene. 2002; 21: 541-52.

Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999; 97: 503-14.

de Langr T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005; 19: 2100-10.

Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973; 41: 181-90.

Wellinger RJ, Ethier K, Labrecque P, Zakian VA. Evidence for a new step in telomere maintenance. Cell. 1996; 85: 423-33.

Walne AJ, Dokal I. Dyskeratosis Congenita: A historical perspective. Mech Ageing Dev. 2007; Oct 30; [Epub ahead of print].

Dokal I. Fanconi’s anaemia and related bone marrow failure syndromes. Br Med Bull. 2006; 77-78: 37-53.

Callen E, Samper E, Ramirez MJ, Creus A, Marcos R, Ortega JJ, Olive T, Badell I, Blasco MA, Surralles J. Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia. Hum Mol Genet. 2002; 11: 439-44.

Adelfalk C, Lorenz M, Serra V, von Zglinicki T, Hirsch-Kauffmann M, Schweiger M. Accelerated telomere shortening in Fanconi anemia fibroblasts – a longitudinal study. FEBS Lett. 2001; 506: 22-6.

Slijepčević P. The role of DNA damage response proteins at telomeres-an “integrative” model. DNA Repair (Amst). 2006; 5: 1299-306.

Bohr VA. Deficient DNA repair in the human progeroid disorder, Werner syndrome. Mutat Res. 2005; 577: 252-9.

Opresko PL, Mason PA, Podell ER, Lei M, Hickson ID, Cech TR, Bohr VA. POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. J Biol Chem. 2005; 280: 32069-80.

Stavropoulos DJ, Bradshaw PS, Li X, Pasic I, Truong K, Ikura M, Ungrin M, Meyn MS. The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum Mol Genet. 2002; 11: 3135-44.

Blasco MA. Telomere length, stem cells and aging. Nat Chem Biol. 2007; 3: 640-9.

Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet. 2001; 358: 472-3.

Oh H, Wang SC, Prahash A, Sano M, Moravec CS, Taffet GE, Michael LH, Youker KA, Entman ML, Schneider MD. Telomere attrition and Chk2 activation in human heart failure. PNAS U S A. 2003; 100: 5378-83.

van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ, van Gilst WH, van Veldhuisen DJ; MERIT-HF Study Group. Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol. 2007; 49: 1459-64.

Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, Rudolph KL. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 2002; 16: 935-42.

O’Sullivan JN, Bronner MP, Brentnall TA, Finley JC, Shen WT, Emerson S, Emond MJ, Gollahon KA, Moskovitz AH, Crispin DA, Potter JD, Rabinovitch PS. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet. 2002; 32: 280-4.

Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003; 361: 393-5.

Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005; 366: 662-4.

Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. PNAS U S A. 2004; 101: 17312-5.

Cherkas LF, Aviv A, Valdes AM, Hunkin JL, Gardner JP, Surdulescu GL, Kimura M, Spector TD. The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell. 2006; 5: 361-5.

Adams J, Martin-Ruiz C, Pearce MS, White M, Parker L, von Zglinicki T. No association between socio-economic status and white blood cell telomere length. Aging Cell. 2007; 6: 125-8.

Lansdorp PM. Stress, social rank and leukocyte telomere length. Aging Cell. 2006; 5: 583-4.

Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology. 2006; 31: 277-87. Acta Medica Academica 2007; 36: 24-34

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Published

2007-06-25

How to Cite

Slijepčević, P. (2007). Telomeres and human disease. Acta Medica Academica, 36(1), 24–34. Retrieved from https://ama.ba/index.php/ama/article/view/26

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Section

Review Articles