In the developing pancreas, self-renewal of progenitors and patterning of cell fates are coordinated to ensure the correct size and cellular makeup of the organ. How this coordination is achieved, however, is not clear. We report that deletion of DNA methyltransferase 1 (Dnmt1) in pancreatic progenitors results in agenesis of the pancreas due to apoptosis of progenitor cells. We show that DNMT1...

DNA methylation is important for controlling gene expression and is catalyzed by DNA methyltransferase (Dnmt1) an enzyme abundant in brain. We recently demonstrated that mice expressing reduced levels of Dnmt1 are protected from cerebral ischemia. Here, we used the cre/loxP system to produce conditional mutants that lack Dnmt 1 in postmitotic neurons of the postnatal brain. We demonstrate that ...

Mammalian DNA methyltransferase 1 (DNMT1) is essential during early embryo development. Consistent with its key role in embryogenesis, depletion of this protein in adult somatic cells promotes severe cellular dysfunctions and cell death. DNMT1 contains a highly evolutionary conserved C-terminal catalytic DNA methyltransferase domain that is thought to be the responsible for the maintenance of C...

In mammalian cells, the replication of genetic and epigenetic information is directly coupled; however, little is known about the maintenance of epigenetic information in DNA repair. Using a laser microirradiation system to introduce DNA lesions at defined subnuclear sites, we tested whether the major DNA methyltransferase (Dnmt1) or one of the two de novo methyltransferases (Dnmt3a, Dnmt3b) ar...

BACKGROUND We use our earlier experimental studies of the catalytic mechanism of DNA methyltransferases to prepare in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for analysis of human epigenome and for the creation of iPS cells. RESULTS We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivatives as novel ...

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...