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TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure.

ABSTRACT: The molecular mechanisms underlying premature ovarian failure, which seriously impacts the physical and psychological health of patients, are not fully understood. Here, we present the role of TRDMT1 in reactive oxygen species-induced granulosa cells death, which is considered an important cause of premature ovarian failure. We found that reactive oxygen species were increased in a H₂O₂ dose-dependent manner and accompanied by the nuclear shuttling of TRDMT1, increased DNA damage and increased apoptosis of granulosa cells. In addition, reactive oxygen species-induced granulosa cells apoptosis could be prevented by the antioxidant N-acetylcysteine or overexpression of TRDMT1. Furthermore, DNA repair following reactive oxygen species induction was severely impaired/enhanced in TRDMT1 mutants, which exhibited reduced/increased RNA m5C methylation activity. Altogether, our results reveal a novel role of TRDMT1 in the regulation of premature ovarian failure through the repair of reactive oxygen species-triggered DNA damage in granulosa cells and provide an improved understanding of the mechanisms underlying granulosa cells apoptosis, which could potentially be useful for future clinical treatments of premature ovarian failure.

SUBMITTER: Sha C

PROVIDER: S-EPMC8221345 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure.

Sha Chunli C Chen Lu L Lin Li L Li Taoqiong T Wei Hong H Yang Meiling M Gao Wujiang W Zhao Dan D Chen Qi Q Liu Yueqin Y Chen Xiaofang X Xu Wenlin W Li Yuefeng Y Zhu Xiaolan X Zhu Xiaolan X

Aging 20210608 11

The molecular mechanisms underlying premature ovarian failure, which seriously impacts the physical and psychological health of patients, are not fully understood. Here, we present the role of TRDMT1 in reactive oxygen species-induced granulosa cells death, which is considered an important cause of premature ovarian failure. We found that reactive oxygen species were increased in a H<sub>2</sub>O<sub>2</sub> dose-dependent manner and accompanied by the nuclear shuttling of TRDMT1, increased DNA ...[more]

PMID: 34100772

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Project description:BackgroundPremature ovarian insufficiency (POI) is a condition characterized by a substantial decline or loss of ovarian function in women before the age of 40. However, the pathogenesis of POI remains to be further elucidated, and specific targeted drugs which could delay or reverse ovarian reserve decline are urgently needed. Abnormal DNA damage repair (DDR) and cell senescence in granulosa cells are pathogenic mechanisms of POI. Ubiquitin-specific protease 14 (USP14) is a key enzyme that regulates the deubiquitylation of DDR-related proteins, but whether USP14 participates in the pathogenesis of POI remains unclear.MethodsWe measured USP14 mRNA expression in granulosa cells from biochemical POI (bPOI) patients. In KGN cells, we used IU1 and siRNA-USP14 to specifically inhibit USP14 and constructed a cell line stably overexpressing USP14 to examine its effects on DDR function and cellular senescence in granulosa cells. Next, we explored the therapeutic potential of IU1 in POI mouse models induced by D-galactose.ResultsUSP14 expression in the granulosa cells of bPOI patients was significantly upregulated. In KGN cells, IU1 treatment and siUSP14 transfection decreased etoposide-induced DNA damage levels, promoted DDR function, and inhibited cell senescence. USP14 overexpression increased DNA damage, impaired DDR function, and promoted cell senescence. Moreover, IU1 treatment and siUSP14 transfection increased nonhomologous end joining (NHEJ), upregulated RNF168, Ku70, and DDB1, and increased ubiquitinated DDB1 levels in KGN cells. Conversely, USP14 overexpression had the opposite effects. Intraperitoneal IU1 injection alleviated etoposide-induced DNA damage in granulosa cells, ameliorated the D-galactose-induced POI phenotype, promoted DDR, and inhibited cell senescence in ovarian granulosa cells in vivo.ConclusionsUpregulated USP14 in ovarian granulosa cells may play a role in POI pathogenesis, and targeting USP14 may be a potential POI treatment strategy. Our study provides new insights into the pathogenesis of POI and a novel POI treatment strategy.

Project description:Premature ovarian failure (POF) is the pathological aging of ovarian tissue. We have previously established a cyclophosphamide-induced mouse POF model and found that cyclophosphamide caused significant damage and apoptosis of mouse ovarian granulosa cells (mOGCs). To systematically explore the molecular biologic evidence of cyclophosphamide-induced mOGC damage at the gene transcription level, RNA-Seqwas used to analyse the differences in mOGC transcriptomes between POF and control (PBS) mice. The sequencing results showed that there were 18765 differential transcription genes between the two groups, of which 192 were significantly up-regulated (log2 [POF/PBS] > 2.0) and 116 were significantly down-regulated (log2 [POF/PBS] < -4.0). Kyoto Encyclopedia of Genes and Genomes analysis found that the neuroactive ligand-receptor interaction pathway was significantly up-regulated and metabolic pathways were significantly down-regulated in the POF group. Gene Ontology analysis showed that the expression of plasma membrane, regulation of transcription and ion binding functions were significantly up-regulated in the POF group, while the expression of cell and cell parts, catalytic activity and single-organism process functions were significantly down-regulated. Finally, protein interaction analysis reveals that in the ovarian steroidogenesis pathway, three Cytochrome P450 family proteins-Cyp1a1, Cyp11a1 and Cyp2u1-interact with Fdx1 to form an interactive network. These three proteins were down-regulated in POF cells, suggesting that they are likely direct regulatory targets of cyclophosphamide. RNA-Seq high-throughput screening analysis demonstrated that cyclophosphamide damage to mOGCs was achieved through its impacts on multiple pathways and on the transcription activities of multiple target genes. Among them, the protein network consisting of the cytochrome P450 family Fdx1, Cyp17a1, Cyp11a1 and Cyp2u1 is a potential new biomarker of mOGC damage in POF in mice.

Project description:BackgroundCyclophosphamide (CTX) is the first-line medication for the treatment of breast cancer, although it potentially leads to severe ovarian dysfunction and even premature ovarian failure (POF). However, the mechanism of CTX-induced POF remains unclear. Mesenchymal stem cell-based therapy has been wildly used for treating numerous diseases. Therefore, our study aims to elucidate the underlying mechanism of CTX-induced POF and to explore the therapeutic effect of human urine stem cells (hUSCs) in POF.MethodsCTX-induced POF or ovarian granulosa cell (GCs) apoptosis were treated with hUSCs and their exosomes in vitro and in vivo. Morphological, histological, and functional alternations were examined using multiple approaches. The effector molecules of hUSC-derived exosomes (hUSC-Exo) were determined by differential expression analysis in the ovaries. The target genes of miRNA were accessed by transcriptome sequencing in GCs, and the underlying mechanisms were further elucidated.ResultshUSCs remarkably inhibited CTX-induced apoptosis and promoted the proliferation of GCs, respectively. In addition, we observed that miR-27b-3p was highly expressed in hUSC-Exo and markedly suppressed CTX-induced GC apoptosis by specifically inhibiting the expression of SLC1A4, a serine transporter, in ovarian GCs, which, in turn, elevated the concentration of the intracellular serine by inhibiting the outflux of cellular serine. More importantly, the knockdown of SLC1A4 or simple supplementation of serine suppressed CTX-induced apoptosis of GCs. Finally, we demonstrated that CTX-induced apoptosis of ovarian GCs was essential for POF by reducing the intracellular serine concentration via elevating the expression of SLC1A4, whereas hUSCs protected against CTX-induced POF via miR-27b-3p/SLC1A4/serine axis-mediated activation of the PI3K/AKT/mTOR signaling pathway.ConclusionsOur study suggests that hUSC-based cell therapy or simple supplementation of serine may provide an efficient therapeutic approach for the prevention and treatment of CTX-induced POF clinically.

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TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure.

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TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure.

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