Open AccessPot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita
Author(s) -
Hua He,
Yang Wang,
Xiaolan Guo,
Sonal Ramchandani,
Jin Ma,
Mei-Feng Shen,
Dennis A. Garcia,
Yibin Deng,
Asha S. Multani,
M. James You,
Sandy Chang
Publication year - 2009
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01400-08
Subject(s) - dyskeratosis congenita , haploinsufficiency , biology , telomerase , phenotype , dna damage , telomere , genetics , dna , dna repair , microbiology and biotechnology , gene
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 mousePot1b gene results in increased apoptosis in highly proliferative tissues. In the setting of telomerase haploinsufficiency, loss ofPot1b 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 forPot1b 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.