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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bleomycin / pharmacology
  • Blood Cells / cytology*
  • Blood Cells / drug effects
  • Blood Cells / metabolism*
  • Blood Cells / radiation effects
  • Cell Death / drug effects
  • Cell Death / radiation effects
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / radiation effects
  • Cell Line
  • Cell Lineage / drug effects
  • Cell Lineage / radiation effects
  • Chromosomes, Human / metabolism
  • DNA Damage
  • DNA Repair* / drug effects
  • DNA Repair* / radiation effects
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Down-Regulation / radiation effects
  • Gamma Rays
  • Genomic Instability / drug effects
  • Genomic Instability / radiation effects
  • Hematopoietic System / cytology
  • Histones / genetics*
  • Humans
  • MicroRNAs / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / radiation effects


  • H2AX protein, human
  • Histones
  • MicroRNAs
  • RNA, Messenger
  • Bleomycin