Telomeres are DNA-protein structures that cap the ends of chromosomes; telomerase
is the enzyme that ensures their integrity. Telomere biology has recently been implicated
in the pathogenesis of a variety of lung diseases, including idiopathic pulmonary
fibrosis, chronic obstructive pulmonary disease/emphysema, and lung cancer. This review
highlights recent discoveries pertaining to the role of telomere biology in lung disease.
Abbreviations:
COPD (chronic obstructive pulmonary disease), IPF (idiopathic pulmonary fibrosis), TERC (telomerase RNA component), TERT (telomerase reverse transcriptase)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Telomeres and telomerase: the means to the end [Nobel lecture].Angew Chem Int Ed Engl. 2010; 49: 7405-7421
- Telomerase discovery: the excitement of putting together pieces of the puzzle [Nobel lecture].Angew Chem Int Ed Engl. 2010; 49: 7422-7439
- DNA ends: just the beginning [Nobel lecture].Angew Chem Int Ed Engl. 2010; 49: 7386-7404
- A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes.Proc Natl Acad Sci U S A. 1988; 85: 6622-6626
- A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena.J Mol Biol. 1978; 120: 33-53
- Cloning yeast telomeres on linear plasmid vectors.Cell. 1982; 29: 245-255
- In vitro reconstitution of the end replication problem.Mol Cell Biol. 2001; 21: 5753-5766
- The stability of broken ends of chromosomes in Zea mays.Genetics. 1941; 26: 234-282
- The telomere syndromes.Nat Rev Genet. 2012; 13: 693-704
- Telomere biology and telomere diseases: implications for practice and research.Hematol Am Soc Hematol Educ Program. 2010; 2010: 30-35
- Telomeres in disease.F1000 Med Rep. 2012; 4: 8
- Telomere diseases.N Engl J Med. 2009; 361: 2353-2365
- Syndromes of telomere shortening.Annu Rev Genomics Hum Genet. 2009; 10: 45-61
- Telomeres and aging.Physiol Rev. 2008; 88: 557-579
- The remaking of chromosomes.Collecting Net. 1938; XIII: 182-195
- Telomerase catalytic subunit homologs from fission yeast and human.Science. 1997; 277: 955-959
- hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization.Cell. 1997; 90: 785-795
- Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types.Hum Mol Genet. 1997; 6: 2011-2019
- Human telomerase contains evolutionarily conserved catalytic and structural subunits.Genes Dev. 1997; 11: 3109-3115
- Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT.Nat Genet. 1997; 17: 498-502
- The RNA component of human telomerase.Science. 1995; 269: 1236-1241
- A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis.Nature. 1989; 337: 331-337
- Purification of Tetrahymena telomerase and cloning of genes encoding the two protein components of the enzyme.Cell. 1995; 81: 677-686
- Protein composition of catalytically active human telomerase from immortal cells.Science. 2007; 315: 1850-1853
- Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation.Mol Cell. 2007; 28: 773-785
- Telomerase in the human organism.Oncogene. 2002; 21: 564-579
- The limited in vitro lifetime of human diploid cell strains.Exp Cell Res. 1965; 37: 614-636
- 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: 181-190
- Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation.Mutat Res. 2012; 730: 12-19
- Telomeric length varies with age and polymorphisms of the MAOA gene promoter in peripheral blood cells obtained from a community in Taiwan.Psychiatr Genet. 2005; 15: 31-35
- Telomere shortening in familial and sporadic pulmonary fibrosis.Am J Respir Crit Care Med. 2008; 178: 729-737
- Telomere reduction in human colorectal carcinoma and with ageing.Nature. 1990; 346: 866-868
- In vivo loss of telomeric repeats with age in humans.Mutat Res. 1991; 256: 45-48
- Telomere shortening with aging in human esophageal mucosa.Age. 1999; 22: 95-99
- Telomere length predicts replicative capacity of human fibroblasts.Proc Natl Acad Sci U S A. 1992; 89: 10114-10118
- Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age.Proc Natl Acad Sci U S A. 1994; 91: 9857-9860
- Obesity, cigarette smoking, and telomere length in women.Lancet. 2005; 366: 662-664
- Substantial variation in qPCR measured mean blood telomere lengths in young men from eleven European countries.Am J Hum Biol. 2011; 23: 228-231
- Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study.Aging Cell. 2008; 7: 451-458
- The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.Cell. 2001; 107: 67-77
- Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961
- Idiopathic pulmonary fibrosis.Orphanet J Rare Dis. 2008; 3: 8
- An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.Am J Respir Crit Care Med. 2011; 183: 788-824
- Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature.Eur Respir Rev. 2012; 21: 355-361
- The epidemiology of interstitial lung diseases.Am J Respir Crit Care Med. 1994; 150: 967-972
- Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study.Chest. 2010; 137: 129-137
- Incidence and prevalence of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2006; 174: 810-816
- Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium.Chest. 2011; 140: 221-229
- Dyskeratosis congenita with pigmentation, dystrophia unguis and leukokeratosis oris.Arch Dermatol Syphilol. 1930; 21: 71-95
- Atrophia cutis reticularis cum pigmentatione, dystrophia unguium et leukokeratosis oris.Ikonogr Dermatol (Hyoto). 1910; 5: 219-223
- A unique case of reticular pigmentation of the skin with atrophy.Arch Dermatol Syphilol. 1926; 13: 685-687
- Dyskeratosis congenita: a historical perspective.Mech Ageing Dev. 2008; 129: 48-59
- Dyskeratosis congenita.J Med Genet. 1988; 25: 843-846
- Fanconi’s anaemia and dyskeratosis congenita as a syndrome.Dermatologica. 1963; 127: 330-342
- Dyskeratosis congenita and familial pancytopenia.JAMA. 1965; 192: 203-208
- Dyskeratosis congenita showing usual interstitial pneumonia.Intern Med. 1994; 33: 226-230
- Bronchoalveolar disease in dyskeratosis congenita.Eur Respir J. 1992; 5: 497-499
- Allogeneic marrow transplantation for aplastic anaemia associated with dyskeratosis congenita.Br J Haematol. 1996; 92: 758-765
- Fatal interstitial pulmonary disease in a patient with dyskeratosis congenita after allogeneic bone marrow transplantation.Bone Marrow Transplant. 1997; 19: 389-392
- Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: case report and systematic literature review.BMC Blood Disord. 2011; 11: 3
- A telomerase component is defective in the human disease dyskeratosis congenita.Nature. 1999; 402: 551-555
- X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions.Nat Genet. 1998; 19: 32-38
- Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure.Blood Cells Mol Dis. 2005; 34: 257-263
- The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.Nature. 2001; 413: 432-435
- Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure.Blood Cells Mol Dis. 2006; 37: 134-136
- Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.Nat Genet. 2004; 36: 447-449
- Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis.Hum Genet. 2001; 108: 299-303
- Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.Proc Natl Acad Sci U S A. 2005; 102: 15960-15964
- Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.N Engl J Med. 2005; 352: 1413-1424
- Dyskeratosis congenita.Hematol Oncol Clin North Am. 2009; 23: 215-231
- Dyskeratosis Congenita (DC) Registry: identification of new features of DC.Br J Haematol. 1998; 103: 990-996
- Telomerase mutations in families with idiopathic pulmonary fibrosis.N Engl J Med. 2007; 356: 1317-1326
- Adult-onset pulmonary fibrosis caused by mutations in telomerase.Proc Natl Acad Sci U S A. 2007; 104: 7552-7557
- A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis.J Med Genet. 2008; 45: 654-656
- A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features.Respir Res. 2012; 13: 64
- Short telomeres are a risk factor for idiopathic pulmonary fibrosis.Proc Natl Acad Sci U S A. 2008; 105: 13051-13056
- Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency.Blood. 2004; 104: 3936-3942
- Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations.Haematologica. 2007; 92: 1013-1020
- Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene.Blood. 2008; 111: 1128-1130
- Pulmonary fibrosis, bone marrow failure, and telomerase mutation.N Engl J Med. 2012; 366: 1551-1553
- Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.PLoS One. 2010; 5: e10680
- Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase.Blood. 2011; 117: 5607-5611
- A spectrum of severe familial liver disorders associate with telomerase mutations.PLoS One. 2009; 4: e7926
- Lung fibrosis, premature graying, and macrocytosis.Am J Respir Crit Care Med. 2012; 186: e8-e9
- TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements.Blood. 2009; 113: 309-316
- Functional characterization of natural telomerase mutations found in patients with hematologic disorders.Blood. 2007; 109: 524-532
- Natural history of pulmonary fibrosis in two subjects with the same telomerase mutation.Chest. 2011; 139: 1203-1209
- Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita.Am J Hum Genet. 2012; 90: 426-433
- The definition of emphysema: report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop.Am Rev Respir Dis. 1985; 132: 182-185
- Prevalence of telomere shortening in familial and sporadic pulmonary fibrosis is increased in men.Am J Respir Crit Care Med. 2009; 179: 1073
- Familial idiopathic pulmonary fibrosis: evidence of lung inflammation in unaffected family members.N Engl J Med. 1986; 314: 1343-1347
- Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.N Engl J Med. 2012; 366: 1968-1977
- Current and novel drug therapies for idiopathic pulmonary fibrosis.Drug Des Devel Ther. 2012; 6: 261-271
- The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report: 2012.J Heart Lung Transplant. 2012; 31: 1073-1086
- Survival after single versus bilateral lung transplantation for high-risk patients with pulmonary fibrosis.Ann Thorac Surg. 2009; 88 (discussion 25–6): 1616-1625
- Lung transplant in idiopathic pulmonary fibrosis.Arch Surg. 2011; 146: 1204-1209
- Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation.Blood. 2012; 120: 3353-3359
- Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.Eur Respir J. 2004; 23: 932-946
- Chronic obstructive pulmonary disease among adults: United States, 2011.MMWR Morb Mortal Wkly Rep. 2012; 61: 938-943
- The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD).PLoS One. 2012; 7: e35567
- The pathogenesis of COPD and IPF: distinct horns of the same devil?.Respir Res. 2012; 13: 3
- COPD as a disease of accelerated lung aging.Chest. 2009; 135: 173-180
- Is the aging process accelerated in chronic obstructive pulmonary disease?.Curr Opin Pulm Med. 2011; 17: 90-97
- Alveolar cell senescence in patients with pulmonary emphysema.Am J Respir Crit Care Med. 2006; 174: 886-893
- Alveolar cell senescence exacerbates pulmonary inflammation in patients with chronic obstructive pulmonary disease.Respiration. 2010; 80: 59-70
- Telomere length and chronic obstructive pulmonary disease: evidence of accelerated aging.J Am Geriatr Soc. 2009; 57: 2372-2374
- Accelerated lung aging: a novel pathogenic mechanism of chronic obstructive pulmonary disease (COPD).Biochem Soc Trans. 2009; 37: 819-823
- Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2009; 179: 566-571
- Telomere shortening in chronic obstructive pulmonary disease.Respir Med. 2009; 103: 230-236
- Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2011; 184: 1358-1366
- Short telomere length, lung function and chronic obstructive pulmonary disease in 46,396 individuals.Thorax. 2012; 68: 429-435
- Telomere shortening in smokers with and without COPD.Eur Respir J. 2006; 27: 525-528
- Telomere length and its associations with oxidized-LDL, carotid artery distensibility and smoking.Front Biosci (Elite Ed). 2010; 2: 1164-1168
- A prospective study of telomere length measured by monochrome multiplex quantitative PCR and risk of lung cancer.Lung Cancer. 2011; 73: 133-137
- Association of telomere length in older men with mortality and midlife body mass index and smoking.J Gerontol A Biol Sci Med Sci. 2011; 66: 815-820
- Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema.Am J Respir Crit Care Med. 2011; 183: 43-49
- A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans.Hum Mol Genet. 2008; 17: 2518-2523
- Telomere length is a determinant of emphysema susceptibility.Am J Respir Crit Care Med. 2011; 184: 904-912
- Cancer statistics, 2012.CA Cancer J Clin. 2012; 62: 10-29
- Differential expression of telomerase reverse transcriptase (hTERT) in lung tumours.Br J Cancer. 2004; 90: 1222-1229
- Telomerase expression in lung preneoplasia and neoplasia.Int J Cancer. 2007; 120: 1835-1841
- Telomerase is not an oncogene.Oncogene. 2002; 21: 494-502
- Absence of cancer-associated changes in human fibroblasts immortalized with telomerase.Nat Genet. 1999; 21: 115-118
- Cancer in dyskeratosis congenita.Blood. 2009; 113: 6549-6557
- Lung cancer susceptibility locus at 5p15.33.Nat Genet. 2008; 40: 1404-1406
- Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.Nat Genet. 2012; 44: 1330-1335
- The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.PLoS Genet. 2010; 6 (:e1001051)
- A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.Am J Hum Genet. 2009; 85: 679-691
- Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations.Nat Genet. 2010; 42: 893-896
- A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese.Nat Genet. 2011; 43: 792-796
- Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.J Natl Cancer Inst. 2010; 102: 959-971
- Functional characterization of CLPTM1L as a lung cancer risk candidate gene in the 5p15.33 locus.PLoS One. 2012; 7: e36116
- Telomere length and the risk of lung cancer.Cancer Sci. 2008; 99: 1385-1389
- Telomere dysfunction: a potential cancer predisposition factor.J Natl Cancer Inst. 2003; 95: 1211-1218
- Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.Lung Cancer. 2009; 66: 157-161
- Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer.Mol Carcinog. 2012; https://doi.org/10.1002/mc.21972
- Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer.Lung Cancer. 2008; 60: 416-425
- Prognostic significance of telomeric repeat length alterations in pathological stage I-IIIA non-small cell lung cancer.Anticancer Res. 2000; 20: 2181-2187
- Telomerase activity in transthoracic fine-needle biopsy aspirates from non-small cell lung cancer as prognostic factor of patients’ survival.Lung Cancer. 2008; 61: 97-103
- Loss of telomerase activity may be a potential favorable prognostic marker in lung carcinomas.Lung Cancer. 2003; 41: 163-169
- Elevation of telomerase activity positively correlates to poor prognosis of patients with non-small cell lung cancer.Cancer Lett. 2006; 240: 148-156
- Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer.Clin Cancer Res. 1999; 5: 2077-2081
- Prognostic impact of telomerase activity in non-small cell lung cancers.Ann Surg. 1999; 230: 715-720
- Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer.Br J Cancer. 2006; 94: 1452-1459
- The diagnostic and prognostic relevance of human telomerase reverse transcriptase mRNA expression detected in situ in patients with nonsmall cell lung carcinoma.Cancer. 2003; 98: 1008-1013
- Cooperative role of telomerase activity and p16 expression in the prognosis of non-small-cell lung cancer.J Clin Oncol. 2002; 20: 254-262
- Correlation between telomerase expression and terminal restriction fragment length ratio in non-small cell lung cancer: an adjusted measurement and its clinical significance.Eur J Cardiothorac Surg. 2004; 26: 425-431
- Novel anticancer therapeutics targeting telomerase.Cancer Treat Rev. 2012;
- Cancer: cancer and telomeres— an ALTernative to telomerase.Science. 2012; 336: 1388-1390
- Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes.Am J Pathol. 2011; 179: 1608-1615
- Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress.Exp Gerontol. 2011; 46: 135-140
- Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization.J Immunol. 2004; 173: 6303-6311
- Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes.J Immunol. 2008; 181: 7400-7406
- The role of CD8+ T-cell replicative senescence in human aging.Immunol Rev. 2005; 205: 147-157
- An analysis of telomere length in sarcoidosis.J Gerontol A Biol Sci Med Sci. 2007; 62: 1199-1203
Article info
Publication history
Published online: April 24, 2013
Accepted:
April 3,
2013
Received in revised form:
April 2,
2013
Received:
January 14,
2013
Footnotes
Conflicts of interest: None.
Identification
Copyright
© 2013 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
