Abstract
Terminally differentiated cells have a reduced capacity to repair double-stranded breaks, but the molecular mechanism behind this downregulation is unclear. Here we find that miR-24 is upregulated during postmitotic differentiation of hematopoietic cell lines and regulates the histone variant H2AX, a protein that has a key role in the double-stranded break response. We show that the H2AX 3' untranslated region contains conserved miR-24 binding sites that are indeed regulated by miR-24. During terminal differentiation, both H2AX mRNA and protein levels are substantially reduced by miR-24 upregulation in in vitro differentiated cells; similar diminished levels are found in primary human blood cells. miR-24-mediated suppression of H2AX renders cells hypersensitive to gamma-irradiation and genotoxic drugs, a phenotype that is fully rescued by overexpression of miR-24-insensitive H2AX. Therefore, miR-24 upregulation in postreplicative cells reduces H2AX and makes them vulnerable to DNA damage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Bleomycin / pharmacology
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Blood Cells / cytology*
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Blood Cells / drug effects
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Blood Cells / metabolism*
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Blood Cells / radiation effects
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Cell Death / drug effects
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Cell Death / radiation effects
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Cell Differentiation* / drug effects
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Cell Differentiation* / radiation effects
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Cell Line
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Cell Lineage / drug effects
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Cell Lineage / radiation effects
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Chromosomes, Human / metabolism
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DNA Damage
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DNA Repair* / drug effects
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DNA Repair* / radiation effects
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Down-Regulation / drug effects
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Down-Regulation / genetics*
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Down-Regulation / radiation effects
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Gamma Rays
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Genomic Instability / drug effects
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Genomic Instability / radiation effects
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Hematopoietic System / cytology
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Histones / genetics*
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Humans
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MicroRNAs / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Up-Regulation / drug effects
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Up-Regulation / radiation effects
Substances
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H2AX protein, human
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Histones
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MicroRNAs
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RNA, Messenger
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Bleomycin