Engineered telomere degradation models dyskeratosis congenita.

Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA.
Genes & Development (Impact Factor: 12.64). 08/2008; 22(13):1773-85. DOI: 10.1101/gad.1679208
Source: PubMed

ABSTRACT Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by cutaneous symptoms, including hyperpigmentation and nail dystrophy. Some forms of DC are caused by mutations in telomerase, the enzyme that counteracts telomere shortening, suggesting a telomere-based disease mechanism. However, mice with extensively shortened telomeres due to telomerase deficiency do not develop the characteristics of DC, raising questions about the etiology of DC and/or mouse models for human telomere dysfunction. Here we describe mice engineered to undergo telomere degradation due to the absence of the shelterin component POT1b. When combined with reduced telomerase activity, POT1b deficiency elicits several characteristics of DC, including hyperpigmentation and fatal bone marrow failure at 4-5 mo of age. These results provide experimental support for the notion that DC is caused by telomere dysfunction, and demonstrate that key aspects of a human telomere-based disease can be modeled in the mouse.

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    ABSTRACT: The single-stranded DNA binding proteins in mouse shelterin, POT1a and POT1b, accumulate at telomeres as heterodimers with TPP1, which binds TIN2 and thus links the TPP1/POT1 dimers with TRF1 and TRF2/Rap1. When TPP1 is tethered to TIN2/TRF1/TRF2, POT1a is thought to block RPA binding to the ss telomeric DNA and prevent ATR kinase activation, Similarly, TPP1/POT1b tethered to TIN2 can control the formation of the correct single-stranded telomeric overhang. Consistent with this view, the telomeric phenotypes following deletion of POT1a/b or TPP1 are phenocopied in TIN2- deficient cells. However, the loading of TRF1 and TRF2/Rap1 are additionally compromised in TIN2 KO cells, leading to added phenotypes. Therefore, it was not excluded that in addition to TIN2, other components of shelterin contribute to the recruitment of TPP1/POT1a,b as suggested by prior reports. To test whether TIN2 is the sole link between TPP1/POT1a,b and telomeres, we defined the TPP1-interaction domain of TIN2 and generated a TIN2 allele that is unable to interact with TPP1 but retains its interaction with TRF1 and TRF2. We demonstrate that cells expressing TIN2ΔTPP1 instead of wild type TIN2 phenocopy the POT1a,b knockout setting without showing additional phenotypes. Thus, these results are consistent with TIN2 being the only mechanism by which TPP1/POT1 heterodimers bind to shelterin and function in telomere protection.
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