title: Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.
abstract: 5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ito
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.forename: Susan C
authors.initials: SC
authors.lastname: Wu
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D000818:Animals; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D053595:Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: C560974:5-carboxylcytosine; C560973:5-formylcytosine; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse