JOURNAL OF HAZARDOUS MATERIALS
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2023
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IF 13.6
Yidan Ma,Xinyi Mu,Rufei Gao,Yan Zhang,Yanqing Geng,Xuemei Chen,Xin Yin,Fangfang Li,Junlin He
Homologous recombination (HR) during early oogenesis repairs programmed double-strand breaks (DSBs) to ensure female fertility and offspring health. The exposure of fetal ovaries to endocrine disrupting chemicals (EDCs) can cause reproductive disorders in the adulthood. The EDC dibutyl phthalate (DBP) is widely distributed in flexible plastic products, leading to ubiquitous human exposure. Here, we report that maternal exposure to DBP caused gross aberrations in meiotic prophase I of fetal oocytes , including delayed progression, impaired DNA damage response, uncoupled localization of DMC1 and RAD51, and decreased HR. However, programmed DSBs were efficiently repaired. DBP exposure negatively regulated lysine crotonylation (Kcr) of MSH6. Similar meiotic defects were observed in fetal ovaries with targeted disruption of Msh6 , and mutation of K544cr of MSH6 impaired its association with Ku70, thereby promoting non-homologous end joining (NHEJ) and inhibiting HR. Unlike mature F1 females, F2 female mice exhibited premature follicular activation, precocious puberty, and anxiety-like behaviors. Therefore, DBP can influence early meiotic events, and Kcr of MSH6 may regulate preferential induction of HR or NHEJ for DNA repair during meiosis.
研究领域:
生殖生物学
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分子遗传学
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发育生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 3
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IF 7.7
Qili Yang,Jinming Kang,Lin Li,Wan Zhang,Dahua Chen,Qinmiao Sun
While the cytosolic localization of cGAS is critical for cells to initiate immune responses and protect cells from viral infections, the activity of cGAS in the nucleus is inhibited to prevent autoimmune responses triggered by self-DNA. Therefore, the dynamically regulated distribution of cGAS in the cytosol and nucleus ensures its precise role in maintaining immune homeostasis. However, the molecular mechanism governing this spatial distribution of cGAS remains unclear. Here, we identify MSH6 as a regulator promoting cGAS nuclear localization by enhancing its association with importin-α proteins, consequently reducing cGAS condensation and activity. We further show that MSH6 attenuates antitumor immunity and that its deficiency in tumor cells leads to an effective tumor eradication by heat-inactivated modified vaccinia virus Ankara. Collectively, our results not only provide insights into understanding how cGAS activity is regulated but also suggest a therapeutic potential for treating MSH6-mutated tumors through the cGAS-mediated signaling pathway.
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DOI
PubMed
高影响因子
Theranostics
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2019
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IF 8.063
Yaodong Chen,Pengfei Liu,Peng Sun,Jian Jiang,Yuanbo Zhu,Tianxiu Dong,Yingzhe Cui,Yuan Tian,Tingting An,Jiuwei Zhang,Zizhuo Li,Xiuhua Yang
Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type. Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM. Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ. However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown. Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6. MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo . Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms. Cu 2 (OH)PO 4 @PAA nanoparticles were fabricated through a hydrothermal method. Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo . Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues. MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM. In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target. Notably, photothermal therapy (PTT) mediated by Cu 2 (OH)PO 4 @PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM. Simultaneously, the prominent MR imaging (T1WI) ability of Cu 2 (OH)PO 4 @PAA could provide visual guidance for PTT. Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.
研究领域:
肿瘤学
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生物医学工程
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分子生物学
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癌症治疗
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纳米技术
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DOI
PubMed
高影响因子
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