Eliminating the impossible

Insights into the pathways that regulate how genes are turned on or off are published online this week in Nature Chemical Biology.

Epigenetic pathways can regulate gene expression by controlling the levels and types of molecular marks on genes and the proteins associated with these genes. DNA methylation-in which small ‘methyl’ groups are attached at or near genes is an important epigenetic pathway in stem cells and cancer. The pathways for how methyl groups are installed on DNA are fairly well characterized, but it remains unclear how these groups are removed from DNA, called DNA demethylation. One model proposes that deaminase enzymes, which are known to convert cytosine bases into uracil bases in DNA, have a central role in DNA demethylation.

Rahul Kohli and colleagues use a biochemical approach to evaluate whether deaminase enzymes can operate on DNA segments containing these epigenetic marks. They found that the marked segments are poor substrates for these enzymes both in the test tube and within cells, which leads them to conclude that DNA demethylation pathways involving deaminases are less probable that other proposed alternatives. This discovery should refocus research efforts for understanding this important regulatory pathway for controlling gene expression.