Essential roles for Pot1b in HSC self-renewal and survival
| Autor: | Sandy Chang, Yang Wang, Mei-Feng Shen |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Aging Telomerase Hematopoiesis and Stem Cells Cell Survival DNA damage Cellular differentiation Immunology Hemoglobinuria Paroxysmal Apoptosis Bone Marrow Cells Mice SCID Biology Biochemistry Mice medicine Animals Progenitor cell Bone Marrow Diseases Cells Cultured Mice Inbred ICR Anemia Aplastic Cell Differentiation Cell Biology Hematology Bone Marrow Failure Disorders Telomere Hematopoietic Stem Cells medicine.disease Shelterin Chromosomes Mammalian Mice Mutant Strains Cell biology DNA-Binding Proteins Female Tumor Suppressor Protein p53 Haploinsufficiency Dyskeratosis congenita DNA Damage |
| Zdroj: | Blood. 118:6068-6077 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Maintenance of mammalian telomeres requires both the enzyme telomerase and shelterin, which protect telomeres from inappropriately activating DNA damage response checkpoints. Dyskeratosis congenita is an inherited BM failure syndrome disorder because of defects in telomere maintenance. We have previously shown that deletion of the shelterin component Pot1b in the setting of telomerase haploinsufficiency results in rapid telomere shortening and fatal BM failure in mice, eliciting phenotypes that strongly resemble human syskeratosis congenita. However, it was unclear why BM failure occurred in the setting of Pot1b deletion. In this study, we show that Pot1b plays an essential role in HSC survival. Deletion of Pot1b results in increased apoptosis, leading to severe depletion of the HSC reserve. BM from Pot1bΔ/Δ mice cannot compete with BM from wild-type mice to provide multilineage reconstitution, indicating that there is an intrinsic requirement for Pot1b the maintenance of HSC function in vivo. Elimination of the p53-dependent apoptotic function increased HSC survival and significantly extended the lifespan of Pot1b-null mice deficient in telomerase function. Our results document for the first time the essential role of a component of the shelterin complex in the maintenance of HSC and progenitor cell survival. |
| Databáze: | OpenAIRE |
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