Sequence permutations in the molecular evolution of DNA methyltransferases

Background: DNA methyltransferases (MTases), unlike MTases acting on other substrates, exhibit sequence permutation. Based on the sequential order of the cofactor-binding subdomain, the catalytic subdomain, and the target recognition domain (TRD), several classes of permutants have been proposed. The majority of known DNA MTases fall into the alpha, beta, and gamma classes. There is only one member of the zeta class known and no members of the delta and epsilon classes have been identified to date. Two mechanisms of permutation have been proposed: one involving gene duplication and in-frame fusion, and the other involving inter-and intragenic shuffling of gene segments. Results: Two novel cases of sequence permutation in DNA MTases implicated in restrictionmodification systems have been identified, which suggest that members of the delta and zeta classes (M. MwoI and M. TvoORF1413P, respectively) evolved from beta-class MTases. This is the first identification of the delta-class MTase and the second known zeta-class MTase (the first zeta-class member among DNA:m(4)C and m(6)A-MTases). Conclusions: Fragmentation of a DNA MTase gene may result from attack of nucleases, for instance when the RM system invades a new cell. Its reassembly into a functional form, the order of motifs notwithstanding, may be strongly selected for, if the cognate ENase gene remains active and poses a threat to the host's chromosome. The cut-and-paste mechanism is proposed for beta- permutation, which is non-circular and involves relocation of one segment of a gene. The circular beta-zeta permutation may be explained both by gene duplication or shuffling of gene fragments. These two mechanisms are not mutually exclusive and probably both played a role in the evolution of permuted DNA MTases.