New research out of Taiwan has found some familiar enzymatic faces are involved in the pathway from 5hmC to cytosine. A talented team of scientists recently showed that two members of the DNA methyltransferase (DNMT) family, DNMT3a and DNMT3b are more than just methyltransferases; they fill a role as dehydroxymethylases as well.
It has already been well established that Tet proteins can convert methylcytosine (5mC) into 5hmC, but finding dehydroxymethylases, or enzymes that convert 5hmC directly back to regular cytosine (C), has been quite elusive. The team from Taiwan ran a series of in vitro assays to search for enzymes that could facilitate the switch from 5hmC to C, and here’s what they learned:
- DNMT3a and DNMT3b, but not DNMT1, can effectively convert 5hmC to C
- Dehydroxymethylation activities were dropped by about 50-60% when catalytic sites of C methylation were mutilated.
- Dehydroxymethylation and methylation reactions likely use the same catalytic sites, but it appears that the redox state of the enzymes determines if they will function as methyltransferases or dehydroxymethylases.
The authors conclude that certain DNMTs do serve as redox state-dependent DNA dehydroxymethylases, which they say represents “a simpler pathway to reduce the levels of DNA hydroxymethylation and methylation”. The bi-directional aspect of DNMT3a and DNMT3b, working as both as DNA methyltransferases and dehydroxymethylases, poses a whole host of new questions about these enzymes and how they regulate genomic modifications during development, carcinogenesis, and gene regulation.
To learn more about the dual lives of DNMTs check out the Journal of Biological Chemistry, August 2012.