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Telomere restoration and extension of proliferative lifespan in dyskeratosis congenita fibroblasts.

作者信息

Westin Erik R, Chavez Elizabeth, Lee Kimberly M, Gourronc Francoise A, Riley Soraya, Lansdorp Peter M, Goldman Frederick D, Klingelhutz Aloysius J

机构信息

Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.

出版信息

Aging Cell. 2007 Jun;6(3):383-94. doi: 10.1111/j.1474-9726.2007.00288.x. Epub 2007 Mar 23.


DOI:10.1111/j.1474-9726.2007.00288.x
PMID:17381549
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2225626/
Abstract

Dyskeratosis congenita (DC), an inherited bone marrow failure syndrome, is caused by defects in telomerase. Somatic cells from DC patients have shortened telomeres and clinical symptoms are most pronounced in organs with a high cell turnover, including those involved in hematopoiesis and skin function. We previously identified an autosomal dominant (AD) form of DC that is caused by mutations in the telomerase RNA component (TER). In this study, we evaluated whether retroviral expression of TER and/or telomerase reverse transcriptase (TERT), the catalytic component of telomerase, could extend telomere length and rescue AD DC cells from a phenotype characteristic of early senescence. Exogenous TER expression, without TERT, could not activate telomerase in AD DC skin fibroblasts. Transduction of TERT alone, however, provided AD DC cells with sufficient telomerase activity to extend average telomere length and proliferative capacity. Interestingly, we found that expression of TER and TERT together resulted in extension of lifespan and higher levels of telomerase and longer telomeres than expression of TERT alone in both AD DC and normal cells. Our results provide evidence that AD DC cells can be rescued from defects in telomere maintenance and proliferation, and that coexpression of TERT and TER together provides a more efficient means to elongate telomeres than expression of TERT alone. Similar strategies may be useful for ameliorating the detrimental effects of telomere shortening in AD DC and other diseases associated with telomerase or telomere defects.

摘要

相似文献

[1]
Telomere restoration and extension of proliferative lifespan in dyskeratosis congenita fibroblasts.

Aging Cell. 2007-6

[2]
Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC.

Exp Dermatol. 2009-6-23

[3]
The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita.

Hum Mol Genet. 2011-11-4

[4]
Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita.

Genes Dev. 2006-10-15

[5]
p53 pathway activation by telomere attrition in X-DC primary fibroblasts occurs in the absence of ribosome biogenesis failure and as a consequence of DNA damage.

Clin Transl Oncol. 2013-9-25

[6]
CRISPR screen identifies CEBPB as contributor to dyskeratosis congenita fibroblast senescence via augmented inflammatory gene response.

G3 (Bethesda). 2023-11-1

[7]
Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells.

Nature. 2011-5-22

[8]
Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients.

Br J Haematol. 2009-3

[9]
Telomerase RNA mutated in autosomal dyskeratosis congenita reconstitutes a weakly active telomerase enzyme defective in telomere elongation.

Cell Cycle. 2005-4

[10]
Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita.

J Allergy Clin Immunol. 2011-11-10

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本文引用的文献

[1]
Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita.

Genes Dev. 2006-10-15

[2]
Functional characterization of natural telomerase mutations found in patients with hematologic disorders.

Blood. 2007-1-15

[3]
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a.

Nature. 2006-9-28

[4]
Methylation of the p16(INK4a) promoter region in telomerase immortalized human keratinocytes co-cultured with feeder cells.

Oncogene. 2006-11-30

[5]
Telomere length homeostasis requires that telomerase levels are limiting.

EMBO J. 2006-2-8

[6]
Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.

Cell. 2005-12-16

[7]
The effect of TERC haploinsufficiency on the inheritance of telomere length.

Proc Natl Acad Sci U S A. 2005-11-22

[8]
Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.

Proc Natl Acad Sci U S A. 2005-11-1

[9]
Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells.

Proc Natl Acad Sci U S A. 2005-10-4

[10]
Shelterin: the protein complex that shapes and safeguards human telomeres.

Genes Dev. 2005-9-15

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