Phosphorylation-mediated DNMT stability and activity. (A) Cigarette carcinogen NNK activates AKT, inhibits GSK3β-mediated DNMT1 phosphorylation at Ser410 and Ser414, thereby leading to DNMT1 protein accumulation. (B) Phosphorylation of DNMT1 by PKCζ reduces its methyltransferase activity. (C) Phosphorylation of DNMT1 at Ser154 by CDK1, 2 and 5 enhances enzymatic activity and protein stability of DNMT1. (D) Phosphorylation of DNMT1 at Ser127 and/or Ser143 decreases its interaction with UHRF1 ubiquitin-like protein and renders DNMT1 less efficient to catalyze the DNA methyltransferase activity at the replication fork.