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A miR-590/Acvr2a/Rad51b axis regulates DNA damage repair during mESC proliferation.

ABSTRACT: Embryonic stem cells (ESCs) enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF), which maintains the self-renewal capability of mouse ESCs (mESCs), significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB) and double-strand break (DSB) damage repair, thus slowing proliferation of mESCs without influencing stemness. miR-590 directly targets Activin receptor type 2a (Acvr2a) to mediate Activin signaling. We identified the homologous recombination-mediated repair (HRR) gene, Rad51b, as a downstream molecule of the miR-590/Acvr2a pathway regulating the SSB and DSB damage repair and cell cycle. Our study shows that a miR-590/Acvr2a/Rad51b signaling axis ensures the stabilization of mESCs by balancing DNA damage repair and rapid proliferation during self-renewal.

SUBMITTER: Liu Q

PROVIDER: S-EPMC4264031 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A miR-590/Acvr2a/Rad51b axis regulates DNA damage repair during mESC proliferation.

Liu Qidong Q Wang Guiying G Chen Yafang Y Li Guoping G Yang Dandan D Kang Jiuhong J

Stem cell reports 20141120 6

Embryonic stem cells (ESCs) enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF), which maintains the self-renewal capability of mouse ESCs (mESCs), significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB) ...[more]

PMID: 25458897

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Project description:BACKGROUND:Breast cancer is one of the leading causes of death in women worldwide. Fast growth is the important character of breast cancer, which makes sure the subsequent metastasize and invasion breast cancer. Golgi related genes GOLPH3 has been reported to regulate many kinds of cancers proliferation. However, its upregulator remains largely unknown. miRNA modulate gene expression by post-transcriptional repression to participate in many signaling pathway of breast cancer cell proliferation. miR-590 has been reported to regulate tumorgenesis and could be regulated by its own target ATF-3. But whether miR-590 can be the modulator of Golgi related genes to regulate the breast cancer proliferation is unclear. METHODS:We performed the bioinformatics analysis of survival rate and expression differences of patients using the data of The Cancer Genome Atlas (TCGA).Both of MTS and BrdU assays were used for cell proliferation analysis. Cell cycle was detected by flow cytometry .qRT-PCR was used for detecting the cell cycle related gene expression. Student's t-test or One way anova was used for statistics. RESULTS:We found the upregulation of GOLPH3 in breast cancer samples compared with normal breast tissues, which also was related to the poor prognosis. Overexpression of GOLPH3 significantly promoted proliferation both of MDA-MB-231 cells (ER negative) and MCF-7 cells (ER positive). We further found that miRNA-590-3p could directly target the 3'-UTR of GOLPH3 mRNA to repress its expression. Overexpression of miR-590-3p inhibited the proliferation of MDA-MB-231 and MCF-7 cells. The rescue experiments indicated that overexpression of GOLPH3 significantly resorted the proliferation inhibited by miR-590-3p. We also found that ATF-3 repressed miR-590-3p expression to modulate miR-590/GOLPH3 pathway to regulate breast cancer cells proliferation. CONCLUSIONS:This study not only suggests that the ATF-3/miR-590/GOLPH3 signaling pathway is critically involved in the proliferation of breast cancer cells, but provides a novel therapeutic target and new insight base on epigenetic regulation for future breast cancer diagnosis and clinical treatment.

Dataset Information

A miR-590/Acvr2a/Rad51b axis regulates DNA damage repair during mESC proliferation.

Publications

A miR-590/Acvr2a/Rad51b axis regulates DNA damage repair during mESC proliferation.

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