Abstract
DNA damage exposure is a major modifier of cell fate in both normal and cancer tissues. In response to DNA damage, myeloid leukemia cells activate a poorly understood terminal differentiation process. Here, we show that the NFκB pathway directly activates expression of the proliferation inhibitor p21 in response to DNA damage in myeloid leukemia cells. In order to understand the role of this unexpected regulatory event, we ablated the NFκB binding site we identified in the p21 promoter, using CRISPR/Cas9-mediated genome editing. We found that NFκB-mediated p21 activation controls DNA damage-induced myeloid differentiation. Our results uncover a p53-independent pathway for p21 activation involved in controlling hematopoietic cell fate.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites
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CRISPR-Cas Systems
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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DNA Damage / genetics*
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Gene Editing
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HL-60 Cells
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Humans
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Leukemia, Myeloid / genetics*
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Leukemia, Myeloid / pathology
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NF-kappa B p50 Subunit / metabolism*
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Promoter Regions, Genetic / genetics
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Transcription Factor RelA / metabolism*
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Tumor Suppressor Protein p53 / metabolism
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U937 Cells
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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NF-kappa B p50 Subunit
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RELA protein, human
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TP53 protein, human
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Transcription Factor RelA
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Tumor Suppressor Protein p53