miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells.
miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells.
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DOI：
10.1038/nsmb.1589
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发表时间：
2009-05
影响因子：
16.8
通讯作者：
中科院分区：
文献类型：
--
作者：
终末分化细胞修复双链断裂（DSB）的能力降低，但这种下调背后的分子机制尚不清楚。我们发现miR-24在造血细胞系有丝分裂后分化过程中持续上调，并调节组蛋白变体H2AX， H2AX是激活细胞周期检查点蛋白并在DSB病灶保留DSB修复因子的关键蛋白。H2AX 3'UTR包含受miR-24调控的保守的miR-24结合位点。在体外分化细胞和人原代血细胞中，通过miR-24上调，H2AX mRNA和蛋白在造血细胞终末分化过程中均大幅减少。miR-24抑制H2AX使细胞对γ辐照和基因毒性药物过敏。在分化细胞中拮抗miR-24可以保护细胞免受DNA损伤诱导的细胞死亡，而在分裂细胞中转染miR-24模拟物会增加染色体断裂和未修复的DNA损伤，并降低对DNA损伤的反应能力。这种DNA修复表型可以通过过表达mir -24不敏感的H2AX来完全挽救。因此，在复制后细胞中，miR-24的上调降低了H2AX，从而使它们极易受到DNA损伤。
Terminally differentiated cells have reduced capacity to repair double strand breaks (DSB), but the molecular mechanism behind this down-regulation is unclear. Here we find that miR-24 is consistently up-regulated during post-mitotic differentiation of hematopoietic cell lines and regulates the histone variant H2AX, a key DSB repair protein that activates cell cycle checkpoint proteins and retains DSB repair factors at DSB foci. The H2AX 3’UTR contains conserved miR-24 binding sites regulated by miR-24. Both H2AX mRNA and protein are substantially reduced during hematopoietic cell terminal differentiation by miR-24 up-regulation both in in vitro differentiated cells and primary human blood cells. miR-24 suppression of H2AX renders cells hypersensitive to γ-irradiation and genotoxic drugs. Antagonizing miR-24 in differentiating cells protects them from DNA damage-induced cell death, while transfecting miR-24 mimics in dividing cells increases chromosomal breaks and unrepaired DNA damage and reduces viability in response to DNA damage. This DNA repair phenotype can be fully rescued by over-expressing miR-24-insensitive H2AX. Therefore, miR-24 up-regulation in post-replicative cells reduces H2AX and thereby renders them highly vulnerable to DNA damage.
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影响因子：
64.5
作者：
Bassing, CH;Suh, H;Alt, FW
通讯作者：
Alt, FW
影响因子：
64.5
作者：
Celeste, A;Difilippantonio, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
DOI：
10.1073/pnas.0404432101
发表时间：
2004-08-10
影响因子：
11.1
作者：
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通讯作者：
Croce, CM
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影响因子：
14.9
作者：
Sun Q;Zhang Y;Yang G;Chen X;Zhang Y;Cao G;Wang J;Sun Y;Zhang P;Fan M;Shao N;Yang X
通讯作者：
Yang X
影响因子：
3.7
作者：
Tzur G;Levy A;Meiri E;Barad O;Spector Y;Bentwich Z;Mizrahi L;Katzenellenbogen M;Ben-Shushan E;Reubinoff BE;Galun E
通讯作者：
Galun E