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Molecular and Cellular Biology, January 2009, p. 229-240, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01400-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita ^,

Hua He,¹ Yang Wang,¹ Xiaolan Guo,¹ Sonal Ramchandani,¹ Jin Ma,¹ Mei-Feng Shen,¹ Dennis A. Garcia,² Yibin Deng,¹ Asha S. Multani,¹ Mingjian James You,³ and Sandy Chang^1,3*

Department of Genetics,¹ Department of Hematopathology, Box 1010, The M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030,³ University of Houston Downtown, One Main Street, Houston, Texas 77002²

Received 5 September 2008/ Returned for modification 25 September 2008/ Accepted 7 October 2008

The Protection of telomeres 1 (POT1) protein is a single-stranded telomere binding protein that is essential for proper maintenance of telomere length. Disruption of POT1 function leads to chromosome instability and loss of cellular viability. Here, we show that targeted deletion of the mouse Pot1b gene results in increased apoptosis in highly proliferative tissues. In the setting of telomerase haploinsufficiency, loss of Pot1b results in depletion of germ cells and complete bone marrow failure due to increased apoptosis, culminating in premature death. Pot1b^–/– mTR^+/– hematopoietic progenitor and stem cells display markedly reduced survival potential in vitro. Accelerated telomere shortening, increased G overhang and elevated number of chromosome end-to-end fusions that initiate an ATR-dependent DNA damage response were also observed. These results indicate an essential role for Pot1b in the maintenance of genome integrity and the long-term viability of proliferative tissues in the setting of telomerase deficiency. Interestingly, these phenotypes closely resemble those found in the human disease dyskeratosis congenita (DC), an inherited syndrome characterized by bone marrow failure, hyperpigmentation, and nail dystrophy. We anticipate that this mouse will serve as a useful model to further understand the pathophysiology of DC.

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* Corresponding author. Mailing address: Department of Genetics, Box 1006, The M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 834-6361. Fax: (703) 834-6363. E-mail: schang{at}mdanderson.org

Published ahead of print on 20 October 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, January 2009, p. 229-240, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01400-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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