Lal Ashish, Pan Yunfeng, Navarro Francisco, Dykxhoorn Derek M, Moreau Lisa, Meire Eti, Bentwich Zvi, Lieberman Judy, Chowdhury Dipanjan
Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Nat Struct Mol Biol. 2009 May;16(5):492-8. doi: 10.1038/nsmb.1589. Epub 2009 Apr 19.
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.
终末分化细胞修复双链断裂的能力降低，但其下调背后的分子机制尚不清楚。在这里，我们发现miR-24在造血细胞系的有丝分裂后分化过程中上调，并调节组蛋白变体H2AX，该蛋白在双链断裂反应中起关键作用。我们表明，H2AX 3'非翻译区包含保守的miR-24结合位点，这些位点确实受miR-24调控。在终末分化过程中，miR-24上调导致体外分化细胞中H2AX mRNA和蛋白水平显著降低；在原代人血细胞中也发现了类似的降低水平。miR-24介导的对H2AX的抑制使细胞对γ射线和基因毒性药物高度敏感，通过过表达对miR-24不敏感的H2AX可完全挽救该表型。因此，复制后细胞中miR-24的上调会降低H2AX水平，使其易受DNA损伤。
