Telomere dysfunction and cell cycle checkpoints in hematopoietic stem cell aging |
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Authors: | Zhenyu Ju Junling Zhang Yingdai Gao Tao Cheng |
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Institution: | (1) School of Medicine, Hangzhou Normal University, Hangzhou, China;(2) Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science, Tianjin, China;(3) State Key Laboratory of Experimental Hematology, Institute of Hematology and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China;(4) Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA |
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Abstract: | Stem cells are believed to be closely associated with tissue degeneration during aging. Studies of human genetic diseases
and gene-targeted animal models have provided evidence that functional decline of telomeres and deregulation of cell cycle
checkpoints contribute to the aging process of tissue stem cells. Telomere dysfunction can induce DNA damage response via
key cell cycle checkpoints, leading to cellular senescence or apoptosis depending on the tissue type and developmental stage
of a specific stem cell compartment. Telomerase mutation and telomere shortening have been observed in a variety of hematological
disorders, such as dyskeratosis congenital, aplastic anemia, myelodysplastic syndromes and leukemia, in which the hematopoietic
stem cells (HSC) are a major target during the pathogenesis. Moreover, telomere dysfunction is able to induce both cell-intrinsic
checkpoints and environmental factors limiting the self-renewal capacity and differentiation potential of HSCs. Crucial components
in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19ARF, play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional
telomere. Therefore, a further understanding of the molecular mechanisms underlying HSC aging may help identity new therapeutic
targets for stem cell-based regenerative medicine. |
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