2
hTERT mutations associated with idiopathic pulmonary fibrosis affect telomerase activity, telomere length, and cell growth by distinct mechanisms.
Aging Cell. 2012 Feb 24
All selected articles haveThis article has been added to your saved articles
You can follow/unfollow articles via MyF1000 or via the article or browse pages.
21 Mar 2012
Darryl Knight
F1000 Respiratory Disorders
University of Newcastle, Australia,
Callaghan, NSW, Australia.
F1000 Respiratory Disorders
University of Newcastle, Australia,
Callaghan, NSW, Australia.
New Finding
DOI: 10.3410/f.14069956.15537056
This study by Tsang and co-workers is interesting as it describes functional consequences of two mutations in the ribonucleoprotein telomerase that have been associated with the development of idiopathic pulmonary fibrosis (IPF).
Telomerase synthesizes specific DNA repeats added to the end of chromosomes...Continue reading
Telomerase synthesizes specific DNA repeats added to the end of chromosomes...Continue reading
This study by Tsang and co-workers is interesting as it describes functional consequences of two mutations in the ribonucleoprotein telomerase that have been associated with the development of idiopathic pulmonary fibrosis (IPF).
Telomerase synthesizes specific DNA repeats added to the end of chromosomes and consists of a protein component, human telomerase reverse transcriptase (hTERT), and an RNA component, RT. Approximately 15-20% of patients with IPF have a family history of the disease and a significant number have mutations in telomerase. Although these mutations have been previously identified, how or if they affect telomere function is not known. To address this, the authors generated mutants corresponding to the V144M missense mutation in the N terminal region (hTERT region) or R865C or R865H mutations that occur in the TR region. All three mutants had similar telomerase activity when transfected into human fibroblasts. The V144M mutant had normal biochemical function but was unable to elongate telomerase. In contrast, the 865 residue is essential for the addition and processing of telomere repeats.
Several interesting observations came from this study: firstly, despite causing a defect in telomere synthesis, overexpression of hTERT V144M, R865C or R865H in human fibroblasts paradoxically extended cell lifespan and this appears to be independent of telomere elongations. Secondly, the R865C mutant appears to maintain telomere length and, as a consequence, may partially overcome normal telomere shortening. While this is a seemingly positive effect, the R865H mutation conveys no such advantage. The authors speculate that this is why the milder mutation was seen in only one case of sporadic IPF, whereas the R865H mutation was found in greater number, including a subset of familial IPF cases.
An important caveat of this study is that patients with these hTERT mutations are heterozygous, expressing both wild-type and mutant hTERT. With the addition of epigenetic and environmental factors, this haploinsufficiency may confer greater risk of apoptosis, with senescence leading to pathological manifestations of the disease. This would be a logical next series of experiments. By showing genetic influences on key mechanisms that lead to (rapid) telomere shortening, this paper sheds light on an important feature of a devastating disease.
Telomerase synthesizes specific DNA repeats added to the end of chromosomes and consists of a protein component, human telomerase reverse transcriptase (hTERT), and an RNA component, RT. Approximately 15-20% of patients with IPF have a family history of the disease and a significant number have mutations in telomerase. Although these mutations have been previously identified, how or if they affect telomere function is not known. To address this, the authors generated mutants corresponding to the V144M missense mutation in the N terminal region (hTERT region) or R865C or R865H mutations that occur in the TR region. All three mutants had similar telomerase activity when transfected into human fibroblasts. The V144M mutant had normal biochemical function but was unable to elongate telomerase. In contrast, the 865 residue is essential for the addition and processing of telomere repeats.
Several interesting observations came from this study: firstly, despite causing a defect in telomere synthesis, overexpression of hTERT V144M, R865C or R865H in human fibroblasts paradoxically extended cell lifespan and this appears to be independent of telomere elongations. Secondly, the R865C mutant appears to maintain telomere length and, as a consequence, may partially overcome normal telomere shortening. While this is a seemingly positive effect, the R865H mutation conveys no such advantage. The authors speculate that this is why the milder mutation was seen in only one case of sporadic IPF, whereas the R865H mutation was found in greater number, including a subset of familial IPF cases.
An important caveat of this study is that patients with these hTERT mutations are heterozygous, expressing both wild-type and mutant hTERT. With the addition of epigenetic and environmental factors, this haploinsufficiency may confer greater risk of apoptosis, with senescence leading to pathological manifestations of the disease. This would be a logical next series of experiments. By showing genetic influences on key mechanisms that lead to (rapid) telomere shortening, this paper sheds light on an important feature of a devastating disease.
Disclosures
None declared
Add Comment
Knight D: F1000Prime Recommendation of [Tsang AR et al., Aging Cell 2012]. In F1000Prime, 21 Mar 2012; DOI: 10.3410/f.14069956.15537056. F1000Prime.com/14069956#eval15537056
F1000Prime Recommendations, Dissents and Comments for [Tsang AR et al., Aging Cell 2012]. In F1000Prime, 19 May 2013; F1000Prime.com/14069956
Only registered/signed-in users can make comments.
Sign in or Subscribe to create your user account and join the discussion.
Sign in or Subscribe to create your user account and join the discussion.
No comments yet.
Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes specific DNA repeats, or telomeric DNA, at the ends of chromosomes. Telomerase is minimally composed of a protein subunit, TERT, and an RNA component, TR. Aberrant telomerase activity has been associated with most human cancers and several premature aging diseases, such as idiopathic pulmonary fibrosis (IPF), a chronic, progressive and fatal lung disease characterized by alveolar epithelial cell damage and fibrosis. Our study focuses on three hTERT mutations that were identified in a subset of patients with IPF, in which these patients also exhibited shorter telomeres compared to age-matched controls. We characterized how three IPF-associated hTERT mutations, V144M, R865C and R865H, affected telomerase function both in vitro and in human cells. We demonstrated that the R865 residue is crucial for repeat addition processivity and thus telomere synthesis in telomerase positive 293 cells and telomerase negative BJ cells, consistent with its location in the hTERT nucleotide binding motif. In contrast, while the V144M mutant did not exhibit any biochemical defects, this mutant was unable to elongate telomeres in human cells. As a result, our studies have identified hTERT V144 and R865 as two critical residues required for proper telomerase function in cells. Together, this may explain how inherited hTERT mutations can lead to shortened telomeres in patients with IPF; and thus, provide further insight into the role of naturally occurring telomerase mutations in the pathophysiology of certain age-related disease states. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
DOI: 10.1111/j.1474-9726.2012.00810.x
PMID: 22364217
