miR-24–mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells

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Abstract
Most terminally differentiated cells have a diminished capacity to respond to and repair DNA damage. Now a microRNA is shown to have a role in this phenotype in blood cells: miR-24 is upregulated in blood cells differentiated in vitro and decreases the levels of H2AX, a histone variant with a key role in the response to DNA double-stranded breaks. 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 γ-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.