Demethylases

Demethylases are enzymes that remove methyl groups from substrates such as nucleic acids and proteins, thereby altering their function and regulation. They participate in epigenetic control, RNA processing, and metabolic signaling by reversing methylation marks that accumulate on DNA, histones, and RNA.

Histone demethylases fall into two main families. The LSD1/2 family (KDM1A/B) is FAD-dependent and can remove mono- and di-methyl groups from certain lysine residues on histones (for example H3K4me1/2 or H3K9me1/2). The JmjC-domain demethylases (KDM2–KDM7) are Fe(II)/α-ketoglutarate-dependent dioxygenases that hydroxylate methylated lysines, enabling demethylation across multiple histone marks. These enzymes regulate gene expression, development, differentiation, and DNA repair.

DNA demethylation involves TET enzymes that oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further oxidation products, with subsequent base-excision repair replacing modified cytosines by unmethylated cytosine. Though not a direct removal of a methyl group, this pathway achieves active DNA demethylation and requires Fe(II) and α-ketoglutarate.

RNA demethylases, such as FTO and ALKBH5, erase methyl marks from RNA nucleotides, notably N6-methyladenosine (m6A). This epitranscriptomic regulation affects mRNA stability, splicing, and translation, linking RNA methylation status to gene expression outcomes.

Implications: Demethylases are key players in development, stem-cell biology, and cancer. Abnormal activity can contribute to oncogenesis and neurological disorders. Researchers use chemical inhibitors and genetic tools to study demethylase function; some inhibitors have been explored for potential therapeutic applications.