miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells.
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.
Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Ashish
A
Lal
Yunfeng
Y
Pan
Francisco
F
Navarro
Derek M
DM
Dykxhoorn
Lisa
L
Moreau
Eti
E
Meire
Zvi
Z
Bentwich
Judy
J
Lieberman
Dipanjan
D
Chowdhury
D001761:Bleomycin / Q000494:pharmacology; D001773:Blood Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects / Q000528:radiation effects; D002877:Chromosomes, Human / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D005720:Gamma Rays; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D006413:Hematopoietic System / Q000166:cytology; D006657:Histones / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
C468783:H2AX protein, human; D006657:Histones; D035683:MicroRNAs; D012333:RNA, Messenger; D001761:Bleomycin