Downregulation of methyltransferase Dnmt2 results in condition-dependent telomere shortening and senescence or apoptosis in mouse fibroblasts.
Dnmt2 is a highly conserved methyltransferase of uncertain biological function(s). As Dnmt2 was considered as a driver of fruit fly longevity and a modulator of stress response, we decided to evaluate the role of Dnmt2 during stress-induced premature senescence in NIH3T3 mouse fibroblasts. Stable knockdown of Dnmt2 resulted in hydrogen peroxide-mediated sensitivity and apoptosis, whereas in the control conditions, senescence was induced. Cellular senescence was accompanied by elevated levels of p53 and p21, decreased telomere length and telomerase activity, increased production of reactive oxygen species and protein carbonylation, and DNA damage. Dnmt2 silencing also promoted global DNA and RNA hypermethylation, and upregulation of methyltransferases, namely Dnmt1, Dnmt3a, and Dnmt3b. Taken together, we show for the first time that Dnmt2 may promote lifespan in the control conditions and survival during stress conditions in mouse fibroblasts.
Laboratory of Cell Biology, University of Rzeszow, Kolbuszowa, Poland.
Anna
A
Lewinska
Laboratory of Cell Biology, University of Rzeszow, Kolbuszowa, Poland.
Jagoda
J
Adamczyk-Grochala
Laboratory of Cell Biology, University of Rzeszow, Kolbuszowa, Poland.
Ewa
E
Kwasniewicz
Department of Genetics, University of Rzeszow, Kolbuszowa, Poland.
Maciej
M
Wnuk
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064113:CRISPR-Cas Systems; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D059506:Telomere Shortening / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
D050759:Cyclin-Dependent Kinase Inhibitor p21; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006861:Hydrogen Peroxide; D017382:Reactive Oxygen Species; D019098:Telomerase; D016159:Tumor Suppressor Protein p53; D000097584:DNA Methyltransferase 3B; C493957:Cdkn1a protein, mouse; C000715535:Dnmt3a protein, mouse; C491786:Dnmt2 protein, mouse; C000619381:Dnmt1 protein, mouse
Dnmt2; apoptosis; genetic instability; senescence; telomere length