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Molecular and Cellular Biology, September 2003, p. 6533-6541, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6533-6541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Targeted Deletion Reveals an Essential Function for the Telomere Length Regulator Trf1

Jan Karlseder,1,{dagger} Leili Kachatrian,2 Hiroyuki Takai,1 Kim Mercer,2 Sunil Hingorani,2,{ddagger} Tyler Jacks,2 and Titia de Lange1*

Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10021,1 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 021392

Received 18 March 2003/ Returned for modification 9 May 2003/ Accepted 16 June 2003

The human telomeric DNA binding factor TRF1 (hTRF1) and its interacting proteins TIN2, tankyrase 1 and 2, and PINX1 have been implicated in the regulation of telomerase-dependent telomere length maintenance. Here we show that targeted deletion of exon 1 of the mouse gene encoding Trf1 causes early (day 5 to 6 postcoitus) embryonic lethality. The absence of telomerase did not alter the Terf1ex1{Delta}/ex1{Delta} lethality, indicating that the phenotype was not due to inappropriate telomere elongation by telomerase. Terf1ex1{Delta}/ex1{Delta} blastocysts had a severe growth defect of the inner cell mass that was accompanied by apoptosis. However, no evidence was found for telomere uncapping causing this cell death; chromosome spreads of Terf1ex1{Delta}/ex1{Delta} blastocysts did not reveal chromosome end-to-end fusions, and p53 deficiency only briefly delayed Terf1ex1{Delta}/ex1{Delta} lethality. These data suggest that murine Trf1 has an essential function that is independent of telomere length regulation.

* Corresponding author. Mailing address: Box 159, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 327-8146. Fax: (212) 327-7147. E-mail: delange{at}mail.rockefeller.edu.

{dagger} Present address: Regulatory Biology, The Salk Institute, La Jolla, CA 92037.

{ddagger} Present address: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160.

Molecular and Cellular Biology, September 2003, p. 6533-6541, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6533-6541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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