DNMT1

DNA (cytosine-5)-methyltransferase 1 (Dnmt1) is an enzyme that catalyzes the transfer of methyl groups to specific CpG sites in DNA, a process called DNA methylation. In humans, it is encoded by the ''DNMT1'' gene. Dnmt1 forms part of the family of DNA methyltransferase enzymes, which consists primarily of DNMT1, DNMT3A, and DNMT3B.

Function

This enzyme is responsible for maintaining DNA methylation, which ensures the fidelity of this epigenetic patterns across cell divisions. In line with this role, it has a strong preference towards methylating CpGs on hemimethylated DNA. However, DNMT1 can catalyze de novo DNA methylation in specific genomic contexts, including transposable elements and paternal imprint control regions. Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.

See also

* DNA methyltransferase

Interactions

DNMT1 has been shown to interact with UHRF1,:
* DMAP1,
* DNMT3A
* DNMT3B,
* HDAC2,
* PCNA,
* RB1. and
* G9A
DNMT1 is highly transcribed during the S phase of the cell cycle when it is required for methylation of the newly generated hemimethylated sites on daughter DNA strands. Its interaction with PCNA and UHRF1 has been implicated in localizing it to the replication fork. The direct co-operation between DNMT1 and G9a coordinates DNA and H3K9 methylation during cell division. This chromatin methylation is necessary for stable repression of gene expression during mammalian development.

Model organisms

Knockout experiments have shown that this enzyme is responsible for the bulk of methylation in mouse cells, and it is essential for embryonic development. It has also been shown that a lack of both maternal and zygotic ''Dnmt1'' results in complete demethylation of imprinted genes in blastocysts.

Clinical significance

DNMT1 plays a critical role in Hematopoietic stem cell (HSC) maintenance. HSCs with reduced DNMT1 fail to self-renew efficiently post-transplantation. It has also been shown to be critical for other stem cell types such as Intestinal stem cells (ISCs) and Mammary stem cells (MaSCs). Conditional deletion of DNMT1 results in overall intestinal hypomethylation, crypt expansion and altered differentiation timing of ISCs, and proliferation and maintenance of MaSCs.

DNMT1 plays a crucial role in maintaining DNA methylation patterns, which are vital for regulating gene expression and maintaining cellular identity in cancer. Dysregulation of DNMT1 can lead to abnormal methylation patterns, contributing to oncogene activation or tumor suppressor gene silencing, thereby promoting cancer progression and metastasis.

Given the role of DNMT1 in maintaining DNA methylation patterns crucial for gene regulation in cancer, the inhibition of DNMT1 by brazilin, a compound from ''Caesalpinia sappan'', is significant. By reducing DNMT1 expression and altering methylation states through activation of p38 MAPK and elevation of p53 in MCF-7 breast cancer cells, brazilin leads to the restoration of p21 expression. This mechanism highlights brazilin's potential as a therapeutic agent to correct epigenetic alterations associated with cancer progression and metastasis.

References

Further reading

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External links

GeneReviews/NCBI/NIH/UW entry on DNMT1-Related Dementia, Deafness, and Sensory Neuropathy