REPLICATIVE DNA METHYLATION AND THE INHERITANCE OF THE DNA METHYLATION PATTERN
Riggs (1975) and Holliday and Pugh (1975) proposed models in which symmetrical methylation of both DNA strands, coupled with a methyltransferase acting only on hemimethylated sites (now widely referred to as maintenance methyltransferase), would lead to stable maintenance of DNA methylation patterns through DNA replication. The methylated patterns of CpG-containing sites were indeed clonally inherited in dividing mouse cells, with a fidelity ~95% per cell generation (Stein et al., 1982; Wigler et al., 1981). We found that DNA synthesis in cells grown in a culture at high cell density pauses at the stage when most short DNA fragments in the lagging strand (Okazaki fragments) are still not ligated (Bashkite et al., 1980; Kiryanov et al., 1980). It turned out that Okazaki fragments are already methylated in plant and animal cells. Thus, the replicative DNA methylation in eukaryotes was discovered, and it was suggested that DNA meth- yltransferase may be a constituent of the DNA replicative complex.