Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to oxidative stress and DNA damage that is accompanied by changes in proliferation-related miRNA expression.
Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to oxidative stress and DNA damage that is accompanied by changes in proliferation-related miRNA expression.
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甲基转移酶DNMT2的水平降低使人的成纤维细胞对氧化应激和DNA损伤，并伴随着增殖相关的miRNA表达的变化。
DOI：
10.1016/j.redox.2017.08.012
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发表时间：
2018-04
期刊：
影响因子：
11.4
通讯作者：
Wnuk M
中科院分区：
文献类型：
--
作者：
Lewinska A;Adamczyk-Grochala J;Kwasniewicz E;Deregowska A;Semik E;Zabek T;Wnuk M
甲基转移酶DNMT 2被认为参与了许多过程的调节，但其生物学意义和潜在的分子机制仍然是难以捉摸的。在本研究中，我们使用WI-38和BJ人成纤维细胞作为体外模型系统来研究基于siRNA的DNMT 2沉默的效果。发现DNMT 2耗尽的细胞对氧化应激条件敏感，如通过活性氧物质的产生增加来判断的，并且对导致细胞增殖抑制的DNA损伤敏感。DNMT 2沉默促进增殖相关和肿瘤抑制miRNA的上调，即miR-28- 3 p、miR-34 a-3 p、miR-30 b-5 p、miR-29 b-3 p、miR-200 c-3 p、miR-28- 5 p、miR-379- 5 p、miR-382- 5 p、miR-194- 5 p、miR-193 b-3 p和miR-409- 3 p。此外，DNMT 2沉默诱导细胞衰老，并且在复制性衰老细胞中DNMT 2水平升高。总之，我们发现DNMT 2可能参与调节人成纤维细胞的细胞增殖和寿命，并推测限制细胞增殖的DNMT 2水平的操纵可能是潜在有用的抗癌策略。DNMT 2沉默促进人成纤维细胞中的氧化应激和DNA损伤。DNMT 2沉默导致增殖相关miRNA的上调。DNMT 2沉默抑制细胞增殖并诱导细胞衰老。DNMT 2水平在复制衰老期间升高。DNMT 2是人成纤维细胞中细胞增殖和寿命的新型调节剂。
Methyltransferase DNMT2 is suggested to be involved in the regulation of numerous processes, however its biological significance and underlying molecular mechanisms remain elusive. In the present study, we have used WI-38 and BJ human fibroblasts as an in vitro model system to investigate the effects of siRNA-based DNMT2 silencing. DNMT2-depleted cells were found to be sensitive to oxidative stress conditions as judged by increased production of reactive oxygen species and susceptible to DNA damage that resulted in the inhibition of cell proliferation. DNMT2 silencing promoted upregulation of proliferation-related and tumor suppressor miRNAs, namely miR-28-3p, miR-34a-3p, miR-30b-5p, miR-29b-3p, miR-200c-3p, miR-28-5p, miR-379-5p, miR-382-5p, miR-194-5p, miR-193b-3p and miR-409-3p. Moreover, DNMT2 silencing induced cellular senescence and DNMT2 levels were elevated in replicatively senescent cells. Taken together, we found that DNMT2 may take part in the regulation of cell proliferation and longevity in human fibroblasts and speculate that the manipulation of DNMT2 levels that limits cell proliferation may be potentially useful anticancer strategy. DNMT2 silencing promotes oxidative stress and DNA damage in human fibroblasts. DNMT2 silencing results in upregulation of proliferation-related miRNAs. DNMT2 silencing inhibits cell proliferation and induces cellular senescence. DNMT2 levels are elevated during replicative senescence. DNMT2 is a novel regulator of cell proliferation and longevity in human fibroblasts.
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影响因子：
3.7
作者：
Coppé JP;Patil CK;Rodier F;Krtolica A;Beauséjour CM;Parrinello S;Hodgson JG;Chin K;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
56.9
作者：
Goll, MG;Kirpekar, F;Bestor, TH
通讯作者：
Bestor, TH
影响因子：
4.8
作者：
Hermann, A;Schmitt, S;Jeltsch, A
通讯作者：
Jeltsch, A
影响因子：
--
作者：
Katoh, M;Curk, T;Shaulsky, G
通讯作者：
Shaulsky, G