Molecular Medicine Israel

Revelation of a mechanism whereby mammalian cells erase critical DNA tags may enhance our understanding of development and disease.

Science 333, 1303–1307 (2011); DOI: 10.1126/science.1210944.
He, Y.-F.,Li, B.-Z., Li, Z.,Liu. P.,Wang, Y., Tang, Q., Ding, J., Jia, Y. Chen, Z.,Li, L.,Sun, Y.  Li, X., Dai, Q., Song, C.-X.,Zhang, K.,He, C.& Xu, G.-L.
“Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA” .

For normal development to proceed, the body silences specific genes at specific times by tagging, with methyl groups, particular cytosine residues on DNA. This process of DNA methylation also suppresses the expression of viral genes and other potentially dangerous genomic elements in healthy cells. Aberrant DNA methylation can, however, contribute to the development and progression of cancer. Now, work by a team led by Guo-Liang Xu at the Chinese  Academy of Sciences in Shanghaihas shed light on how cells remove methyl groups from DNA. The concerted actions of two enzymes may be all that cells need to clean their genomic slate.

Xu and colleagues first showed that Tet (ten eleven translocation) enzymes, which were previously known to convert the modified cytosine residue called 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), can also convert either 5mC or 5hmC to 5-carboxylcytosine (5caC). They further demonstrated that the enzyme thymine-DNA glycosylase (TDG), which is essential for embryonic development, can then recognize and excise these 5caC tags so that they can be replaced with unmethylated cytosines.

The team thinks that targeted manipulation of this molecular mechanism might eventually find applications in reversing the aberrant DNA methylation often seen in cancer cells or perhaps enable more effective manipulation of stem cells used in regenerative medicine. 


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