miR-24–mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells
Identifieur interne : 001B11 ( Main/Exploration ); précédent : 001B10; suivant : 001B12miR-24–mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells
Auteurs : Ashish Lal [États-Unis] ; Yunfeng Pan [États-Unis] ; Francisco Navarro [États-Unis] ; Derek M. Dykxhoorn [États-Unis] ; Lisa Moreau [États-Unis] ; Eti Meire [Israël] ; Zvi Bentwich [Israël] ; Judy Lieberman [États-Unis] ; Dipanjan Chowdhury [États-Unis]Source :
- Nature Structural & Molecular Biology [ 1545-9993 ] ; 2009-05.
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.
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.
Url:
DOI: 10.1038/nsmb.1589
Affiliations:
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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.</div><div type="abstract" xml:lang="eng">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.</div></front></TEI><affiliations><list><country><li>Israël</li><li>États-Unis</li></country><region><li>Massachusetts</li></region></list><tree><country name="États-Unis"><region name="Massachusetts"><name sortKey="Lal, Ashish" sort="Lal, Ashish" uniqKey="Lal A" first="Ashish" last="Lal">Ashish Lal</name></region><name sortKey="Chowdhury, Dipanjan" sort="Chowdhury, Dipanjan" uniqKey="Chowdhury D" first="Dipanjan" last="Chowdhury">Dipanjan Chowdhury</name><name sortKey="Chowdhury, Dipanjan" sort="Chowdhury, Dipanjan" uniqKey="Chowdhury D" first="Dipanjan" last="Chowdhury">Dipanjan Chowdhury</name><name sortKey="Dykxhoorn, Derek M" sort="Dykxhoorn, Derek M" uniqKey="Dykxhoorn D" first="Derek M" last="Dykxhoorn">Derek M. Dykxhoorn</name><name sortKey="Lieberman, Judy" sort="Lieberman, Judy" uniqKey="Lieberman J" first="Judy" last="Lieberman">Judy Lieberman</name><name sortKey="Lieberman, Judy" sort="Lieberman, Judy" uniqKey="Lieberman J" first="Judy" last="Lieberman">Judy Lieberman</name><name sortKey="Moreau, Lisa" sort="Moreau, Lisa" uniqKey="Moreau L" first="Lisa" last="Moreau">Lisa Moreau</name><name sortKey="Navarro, Francisco" sort="Navarro, Francisco" uniqKey="Navarro F" first="Francisco" last="Navarro">Francisco Navarro</name><name sortKey="Pan, Yunfeng" sort="Pan, Yunfeng" uniqKey="Pan Y" first="Yunfeng" last="Pan">Yunfeng Pan</name></country><country name="Israël"><noRegion><name sortKey="Meire, Eti" sort="Meire, Eti" uniqKey="Meire E" first="Eti" last="Meire">Eti Meire</name></noRegion><name sortKey="Bentwich, Zvi" sort="Bentwich, Zvi" uniqKey="Bentwich Z" first="Zvi" last="Bentwich">Zvi Bentwich</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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