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

Ashish Lal, Yunfeng Pan, Francisco Navarro, Derek M Dykxhoorn, Lisa Moreau, Eti Meire, Zvi Bentwich, Judy Lieberman, Dipanjan Chowdhury

Research output: Contribution to journalArticle

206 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)492-498
Number of pages7
JournalNature Structural and Molecular Biology
Volume16
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

Fingerprint

DNA Repair
Blood Cells
Down-Regulation
Up-Regulation
3' Untranslated Regions
Histones
DNA Damage
Proteins
Binding Sites
Phenotype
Cell Line
Messenger RNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology
  • Medicine(all)

Cite this

MiR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. / Lal, Ashish; Pan, Yunfeng; Navarro, Francisco; Dykxhoorn, Derek M; Moreau, Lisa; Meire, Eti; Bentwich, Zvi; Lieberman, Judy; Chowdhury, Dipanjan.

In: Nature Structural and Molecular Biology, Vol. 16, No. 5, 01.05.2009, p. 492-498.

Research output: Contribution to journalArticle

Lal, A, Pan, Y, Navarro, F, Dykxhoorn, DM, Moreau, L, Meire, E, Bentwich, Z, Lieberman, J & Chowdhury, D 2009, 'MiR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells', Nature Structural and Molecular Biology, vol. 16, no. 5, pp. 492-498. https://doi.org/10.1038/nsmb.1589
Lal, Ashish ; Pan, Yunfeng ; Navarro, Francisco ; Dykxhoorn, Derek M ; Moreau, Lisa ; Meire, Eti ; Bentwich, Zvi ; Lieberman, Judy ; Chowdhury, Dipanjan. / MiR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. In: Nature Structural and Molecular Biology. 2009 ; Vol. 16, No. 5. pp. 492-498.
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