Premium
The allosteric regulation of Dnmt1 catalysis and processivity by nucleic acids
Author(s) -
Reich Norbert O
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a77
Subject(s) - processivity , allosteric regulation , dna , nucleic acid , chemistry , biochemistry , dna methylation , dna replication , methylation , biology , enzyme , gene expression , gene
The mechanisms whereby the essential mammalian patterns of post‐replicative DNA methylation are determined remain obscure. Our recent work shows how the binding of DNA at an allosteric site on Dnmt1 significantly alters the enzyme’s activity and processivity. These results bear on how various cellular RNA and DNA molecules can direct the function of DNA methyltransferases. Dnmt1 shows poor activity with unmethylated substrates, and a single cycle of catalysis releases this inhibition. Interestingly, this release of inhibition does not require AdoMet‐dependent methylation since it was observed during the cofactor free cytosine C 5 exchange reaction. Thus, proximal methylated DNA is not needed for this activation. Dnmt1’s processive methylation is dramatically responsive to the type of nucleic acid bound at the active site, and the allosteric site. Single stranded nucleic acids completely stop the processive catalysis. In contrast, the methylation of hemimethylated DNA is inhibited only if the allosteric site is occupied with hemimethylated DNA, with no changes in processivity observed with unmethylated DNA or poly (dA‐dT). Our in vitro results provide a plausible mechanism whereby various nucleic acids modulate Dnmt1 function. The recent reports on RNA‐directed methylation observed in cells and in vivo may rely on similar mechanisms.