Essential role of limiting telomeres in the pathogenesis of Werner syndrome

Nature Genetics
Sandy ChangRonald A DePinho

Abstract

Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relat...Continue Reading

References

Apr 12, 1996·Science·C E YuG D Schellenberg
Oct 28, 1998·Proceedings of the National Academy of Sciences of the United States of America·M Lebel, P Leder
Nov 11, 1999·Clinical and Experimental Immunology·H KanekoN Kondo
Apr 11, 2000·Molecular and Cellular Biology·D B LombardL Guarente
Nov 23, 2000·Nature·G M Martin, J Oshima
Dec 6, 2000·The Journal of Experimental Medicine·F A GoytisoloM A Blasco
Feb 15, 2001·Cytogenetics and Cell Genetics·R MelcherH Hoehn
Aug 16, 2002·The Journal of Biological Chemistry·Patricia L OpreskoVilhelm A Bohr
Mar 4, 2003·Nature Reviews. Cancer·Ian D Hickson
Sep 6, 2003·Current Biology : CB·Hiroyuki TakaiTitia de Lange
Nov 11, 2003·Nature·Fabrizio d'Adda di FagagnaStephen P Jackson

❮ Previous
Next ❯

Citations

Jan 11, 2005·The Journal of Pathology·Kathryn Maddison, Alan R Clarke
Jul 31, 2007·Cellular and Molecular Life Sciences : CMLS·L S Cox, R G A Faragher
Jun 20, 2008·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Maria Grazia Andreassi
Jan 11, 2008·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Tobias ElseDavid O Ferguson
Apr 7, 2006·Journal of Neuro-oncology·E MartonP Longatti
Nov 19, 2008·Transgenic Research·Fernando G OsorioJosé M P Freije
Feb 21, 2013·Current Osteoporosis Reports·Monique BethelMelissa A Kacena
Apr 7, 2005·Molecular Aspects of Medicine·Ken Watanabe, Akinori Hishiya
Jun 2, 2005·Mutation Research·Sandy Chang
Jun 11, 2005·Mutation Research·Ali Ozgenc, Lawrence A Loeb
May 27, 2005·Mutation Research·Vilhelm A Bohr
Dec 18, 2007·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Takako KawasakiShuji Ogino
Sep 19, 2007·Nature Chemical Biology·Maria A Blasco
Sep 3, 2008·Nature Clinical Practice. Cardiovascular Medicine·Tohru Minamino, Issei Komuro
Aug 7, 2009·Nature Reviews. Cancer·Wai Kit Chu, Ian D Hickson
Sep 2, 2005·Nature Reviews. Genetics·Maria A Blasco
Sep 12, 2012·Nature Reviews. Genetics·Mary Armanios, Elizabeth H Blackburn
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Sagar Sengupta, Curtis C Harris
Apr 24, 2007·Nature Reviews. Molecular Cell Biology·Brian A KudlowRaymond J Monnat
Sep 22, 2007·Nature Reviews. Molecular Cell Biology·Eric Gilson, Vincent Géli
Feb 4, 2010·Nature Reviews. Molecular Cell Biology·Roderick J O'Sullivan, Jan Karlseder
May 17, 2012·Nature Reviews. Molecular Cell Biology·Ergün Sahin, Ronald A DePinho
Jun 2, 2006·Nature Structural & Molecular Biology·Jan Karlseder
Dec 6, 2006·Nature Structural & Molecular Biology·Nancy Maizels
Aug 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Hong JiangK Lenhard Rudolph
Aug 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·R Tanner HagelstromSusan M Bailey
May 9, 2006·Antioxidants & Redox Signaling·Yousin Suh, Jan Vijg
Dec 3, 2008·Cardiovascular Research·Liza S M WongPim van der Harst
Dec 13, 2005·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Terence DavisDavid Kipling
May 10, 2006·Nucleic Acids Research·Susan M Bailey, John P Murnane
Nov 17, 2007·Nucleic Acids Research·Robert M Brosh, Vilhelm A Bohr
Dec 28, 2007·Nucleic Acids Research·Jonathan Kenyon, Stanton L Gerson
Sep 11, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Laurent MassipMichel Lebel
Dec 12, 2012·Proceedings. Biological Sciences·Christina BauchSimon Verhulst

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.