Aberrant DNA methylation is often associated with cancer and the formation of tumors; however, the underlying mechanisms, in particular the recruitment and regulation of DNA methyltransferases remain largely unknown. In this study, we identified USP7 as an interaction partner of Dnmt1 and UHRF1 in vivo. Dnmt1 and USP7 formed a soluble dimer complex that associated with UHRF1 as a trimeric compl...

Molecule-targeted therapy, such as sorafenib, is one of the effectively therapeutic options for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib has been found in some HCC patients, resulting in poor prognosis. It is reported that PD-L1 and DNA methyltransferases (DNMTs) contribute to drug resistance. In this study, by inducing sorafenib-resistant HCC cell line...

Epigenetic inheritance in mammals relies in part on robust propagation of DNA methylation patterns throughout development. We show that the protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1), also known as NP95 in mouse and ICBP90 in human, is required for maintaining DNA methylation. UHRF1 colocalizes with the maintenance DNA methyltransferase protein DNMT1 throughout S p...

We previously reported that heterozygous DNA methyltransferase 1-deficient (Dnmt1(+/-)) mice maintain T-cell immune function and DNA methylation levels with aging, whereas controls develop autoimmunity, immune senescence, and DNA hypomethylation. We therefore compared survival, cause of death, and T-cell DNA methylation gene expression during aging in Dnmt1(+/-) mice and controls. No difference...

DNA methylation regulates gene expression through a complex network of protein-protein and protein-DNA interactions in chromatin. The maintenance methylase, DNMT1 (DNA methyltransferase 1), is a prominent enzyme in the process that is linked to DNA replication and drives the heritable nature of epigenetic modifications. The mechanistic details that explain how DNMT1 catalytic action is directed...

A major obstacle toward understanding how patterns of abnormal mammalian cytosine DNA methylation are established is the difficulty in quantitating the de novo methylation activities of DNA methyltransferases (DNMT) thought to catalyze these reactions. Here, we describe a novel method, using native human CpG island substrates from genes that frequently become hypermethylated in cancer, which ge...

Cortical DNA-methyltransferase 1 (DNMT1) is preferentially expressed in interneurons secreting GABA where it very likely contributes to promoter CpG island hypermethylation, thus causing a down-regulation of promoter functions. To consolidate and expand on previous findings that, in the cortex of schizophrenia (SZ) brains, glutamic acid decarboxylase 67 (GAD67) expression is down-regulated wher...

Drug-induced aberrant DNA methylation is the first identified epigenetic marker involved in chemotherapy resistance. Understanding how the aberrant DNA methylation is acquired would impact cancer treatment in theory and practice. In this study we systematically investigated whether and how ERα propelled aberrant global DNA hypermethylation in the context of breast cancer drug resistance. Our da...

In mammalian heterochromatin, cytosine bases of CpG dinucleotides are symmetrically modified by methylation. Patterns of CpG methylation are maintained by the action of Dnmt1, the mammalian maintenance cytosine methyltransferase enzyme. We genetically manipulated the levels of CpG methylation and found that extensive chromatin alterations occur in pericentric heterochromatin. Homozygous mutatio...

DNA methylation is an important epigenetic mechanism that ensures correct gene expression and maintains genetic stability. DNA methyltransferase 1 (DNMT1) is the primary enzyme that maintains DNA methylation during replication. Dysregulation of DNMT1 is implicated in a variety of diseases. DNMT1 protein stability is regulated via various post-translational modifications, such as acetylation and...