Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1(-/-) mice
Autor: | Jan H.J. Hoeijmakers, Ivo P. Touw, Astrid S. Lalai, Joanna M Prasher, Laura J. Niedernhofer, Robert Ploemacher, Claudia Heijmans-Antonissen |
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Přispěvatelé: | Hematology, Molecular Genetics |
Rok vydání: | 2005 |
Předmět: |
Senescence
DNA Repair DNA repair Biology Article General Biochemistry Genetics and Molecular Biology Mice Fanconi anemia medicine Animals Cell Lineage Erythropoiesis Molecular Biology Cells Cultured Cell Proliferation Mice Knockout Progeria General Immunology and Microbiology General Neuroscience Cell Differentiation Endonucleases Hematopoietic Stem Cells medicine.disease Molecular biology Blood Cell Count Hematopoiesis DNA-Binding Proteins medicine.anatomical_structure Liver Bone marrow ERCC1 Gene Deletion Nucleotide excision repair |
Zdroj: | EMBO Journal, 24(4), 861-871. Wiley-Blackwell |
ISSN: | 0261-4189 |
Popis: | The ERCC1-XPF heterodimer is a structure-specific endonuclease involved in both nucleotide excision repair and interstrand crosslink repair. Mice carrying a genetic defect in Ercc1 display symptoms suggestive of a progressive, segmental progeria, indicating that disruption of one or both of these DNA damage repair pathways accelerates aging. In the hematopoietic system, there are defined age-associated changes for which the cause is unknown. To determine if DNA repair is critical to prolonged hematopoietic function, hematopoiesis in Ercc1−/− mice was compared to that in young and old wild-type mice. Ercc1−/− mice (3-week-old) exhibited multilineage cytopenia and fatty replacement of bone marrow, similar to old wild-type mice. In addition, the proliferative reserves of hematopoietic progenitors and stress erythropoiesis were significantly reduced in Ercc1−/− mice compared to age-matched controls. These features were not seen in nucleotide excision repair-deficient Xpa−/− mice, but are characteristic of Fanconi anemia, a human cancer syndrome caused by defects in interstrand crosslink repair. These data support the hypothesis that spontaneous interstrand crosslink damage contributes to the functional decline of the hematopoietic system associated with aging. |
Databáze: | OpenAIRE |
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