DNA Demethylation Pathway - the 7th Base
Source:
Time: 2011-08-12
The prevalent DNA modification in higher organisms is the methylation of cytosine to 5-methylcytosine (5mC), which is partially converted to 5-hydroxymethylcytosine (5hmC) by the Tet family of dioxygenases. Despite their significance in epigenetic regulation, it is unclear how these cytosine modifications are reversed. Recently, a team of researchers, led by XU Guoliang, at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, provided direct evidences that 5mC (the 5th base) and 5hmC(the 6th base) in DNA are oxidized to 5-carboxylcytosine (5caC, the 7th base) by Tet dioxygenases. 5caC is specifically recognized and excised by thymine-DNA glycosylase (TDG). Their data suggest that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation.
To detect the 7th base (5caC) in vitro and in vivo, HE Yufei and his colleagues, under the supervision of Dr. XU Guoliang, used biochemistry, chemistry and genetic methods. They found that Tet dioxygenases could oxidize 5mC and 5hmC to5caC in DNA in vitro and in cultured cells. In addition, one of glycosylases, thymine-DNA glycosylase (TDG), could specifically recognize and excise the newly identified base, 5caC. Depletion of TDG in mouse ES cells leads to accumulation of 5caC to a readily detectable level. Thus, they provide a possible pathway for active DNA demethylation (5mC→5hmC→5caC→C).
This work entitled “Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA” was published online in Science on August 4th, 2011, before its appearance in print.
This study was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology, National Natural Science Foundation of China.
AUTHOR CONTACT:
XU Guoliang
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Model for DNA demethylation promoted by Tet and TDG. Consecutive hydroxylation of 5mC generates 5caC that is recognized and excised by TDG. The resulting abasic site in turn induces the base excision repair pathway, leading to the incorporation of unmethylated cytosines. (Image provided by Dr. XU Guoliang)