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


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 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.

SUBMITTER: Lal A 

PROVIDER: S-EPMC2853019 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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

Lal Ashish A   Pan Yunfeng Y   Navarro Francisco F   Dykxhoorn Derek M DM   Moreau Lisa L   Meire Eti E   Bentwich Zvi Z   Lieberman Judy J   Chowdhury Dipanjan D  

Nature structural & molecular biology 20090419 5


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 te  ...[more]

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