DNMT1

DNMT1, or DNA (cytosine-5)-methyltransferase 1, is a maintenance DNA methyltransferase in mammals that copies CpG methylation patterns to the daughter strand during DNA replication. It preferentially methylates hemi-methylated CpG sites generated after replication, preserving epigenetic information through cell division. By doing so, DNMT1 helps regulate gene expression, imprinting, and genome stability.

Structure and regulation: DNMT1 contains an N-terminal regulatory region, including the replication foci targeting sequence and a CXXC-type zinc finger, and a C-terminal catalytic methyltransferase domain. A regulatory autoinhibitory region (RFTS) can suppress activity in the absence of proper targeting; interaction with PCNA via a PIP box localizes DNMT1 to replication forks. The enzyme is stabilized and recruited by UHRF1, which recognizes hemi-methylated DNA and histone marks such as H3K9me2/3, linking DNA methylation to chromatin state.

Mechanism: During S phase, UHRF1 binds hemi-methylated CpG and recruits DNMT1 to newly synthesized DNA; DNMT1 then methylates the daughter strand, restoring symmetric CpG methylation.

Genetics and clinical relevance: The DNMT1 gene is located on chromosome 19p13.2 in humans. DNMT1 is essential for development; loss of function is embryonically lethal in mice and embryos, and dysregulation of DNMT1 has been observed in various cancers and neurodegenerative disorders. Epigenetic therapies targeting DNMT1 include nucleoside inhibitors such as decitabine and azacitidine, which deplete DNMT1 activity.