The mechanisms by which the post-replicative DNA mismatch repair (MMR) enzyme MSH2 is involved in the complex response mechanisms to UV damage are yet to be clarified. Here, we show increased levels of MSH2 mRNA in malignant melanoma, metastases of melanoma, and melanoma cell (MeWo) lines as compared with melanocytic nevi or primary cultured benign melanocytes. UV-B treatment modulated MSH2 expression and silencing of MSH2 gene expression using small interfering RNA technology regulated UV-B-induced cell cycle arrest and apoptosis in human MeWo. We show that MSH2-deficient non-malignant mouse fibroblasts (MEF-/-) are partially resistant against UV-B-induced apoptosis and show reduced S-Phase accumulation. In addition, we show that an Msh2 point mutation (MEFGA) that affects MMR does not affect UV-B-induced apoptosis. In conclusion, we demonstrate that MSH2 modulates in human melanocytes both UV-B-induced cell cycle regulation and apoptosis, most likely via independent, uncoupled mechanisms.

译文

复制后DNA错配修复 (MMR) 酶MSH2参与紫外线损伤的复杂反应机制的机制尚未阐明。在这里,与黑素细胞痣或原代培养的良性黑素细胞相比,我们显示了恶性黑素瘤,黑素瘤转移和黑素瘤细胞 (MeWo) 细胞系中MSH2 mRNA的水平升高。Uv-b处理通过小干扰RNA技术调节MSH2的表达和MSH2基因表达的沉默,调节uv-b诱导的人MeWo细胞周期停滞和凋亡。我们显示MSH2-deficient非恶性小鼠成纤维细胞 (MEF-/-) 对uv-b诱导的细胞凋亡具有部分抗性,并显示出减少的S期积累。此外,我们显示影响MMR的Msh2点突变 (MEFGA) 不会影响uv-b诱导的细胞凋亡。总之,我们证明MSH2在人黑素细胞中同时调节uv-b诱导的细胞周期调节和凋亡,很可能是通过独立的非耦合机制。

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