MCB
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Du, X.
Right arrow Articles by Johnson, F. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Du, X.
Right arrow Articles by Johnson, F. B.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2004, p. 8437-8446, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8437-8446.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Telomere Shortening Exposes Functions for the Mouse Werner and Bloom Syndrome Genes

Xiaobing Du,1 Johnny Shen,1 Nishan Kugan,1 Emma E. Furth,1 David B. Lombard,2 Catherine Cheung,3 Sally Pak,3 Guangbin Luo,4 Robert J. Pignolo,5 Ronald A. DePinho,6,7 Leonard Guarente,3 and F. Brad Johnson1*

Department of Pathology and Laboratory Medicine,1 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,5 Department of Pathology, Brigham and Women's Hospital,2 Department of Medical Oncology, Dana-Farber Cancer Institute,6 Departments of Medicine and Genetics, Harvard Medical School, Boston,7 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts,3 Department of Genetics, Case Western Reserve University, Cleveland, Ohio4

Received 28 May 2004/ Accepted 18 July 2004

The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.

* Corresponding author. Mailing address: 405A Stellar Chance Laboratories, 422 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104-6100. Phone: (215) 573-5037. Fax: (215) 573-6317. E-mail: johnsonb{at}mail.med.upenn.edu.

Molecular and Cellular Biology, October 2004, p. 8437-8446, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8437-8446.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. J. Virol. Eukaryot. Cell
Microbiol. Mol. Biol. Rev. Clin. Vaccine Immunol. All ASM Journals

Copyright © 2004 by the American Society for Microbiology. All rights reserved.