DNMT1

Official Full Name

DNA methyltransferase 1

Organism

Homo sapiens

GeneID

1786

Background

This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

Synonyms

AIM; DNMT; MCMT; CXXC9; HSN1E; ADCADN; m.HsaI;

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Detailed Information

DNA methylation is mediated by DNA methyltransferases (DNMTs), which are composed of the maintenance methyltransferase DNMT1, and de novo methyltransferases DNMT3A and DNMT3B. These enzymes play important physiological roles in mammalian development, genome stability and cell fate determination where DNMT3A and DNMT3B establish methylation at CpG dinucleotides, and the DNA methylation patterns are maintained by DNMT1 during cellular proliferation. DNMT1 is required for faithful maintenance of DNA methylation patterns, as well as aberrant silencing of tumor suppressor genes in human cancer cells indispensable for their cell cycle progression, proliferation and survival. DNMT1 is involved in tumorigenesis of several cancer types including hematological cancers (lymphomas and leukemias) and multiple solid tumors (liver, gastric, breast, bone).

Biological Functions of DNMT1

DNMT1 is a key enzyme, which methylates CpG islands located near the regulatory regions of genes, thus affecting the transcription of specific genes involved in cancer development and progression. The C-terminal catalytic domain of DNMT1 is under tight allosteric control by several N-terminal domains, including the RFTS domain (RFTD), which plays three roles in the regulation of DNMT1: First, it blocks the catalytic pocket, thus reducing the catalytic activity of DNMT1. Second, it interacts with other proteins including UHRF1, which can target DNMT1 to replication foci or heterochromatin. Third, interaction with UHRF1 can alleviate the RFTD mediated allosteric repression of DNMT1 activity. Wu et al. show that deletion of the RFTS domain results in converse changes of DNA methylation which mimic the alterations observed in cancer cells. On the one hand, the activity of DNMT1 is increased leading to DNA hypermethylation at sites, where DNMT1 is targeted in an RFTD independent manner, for example at the promoter region of tumor suppressor genes. On the other hand, deletion of RFTD disrupts the interaction of DNMT1 and UHRF1 resulting in the loss of heterochromatic localization DNMT1 and hypomethylation of heterochromatic SAT2 elements. It can be speculated that somatic DNMT1 mutations in cancer cells that disrupt the folding of the RFTS domain could have similar effects.

Figure 1. Schematic picture of the changes in DNA methylation caused by the loss-of-function of the RFTS domain (RFTD) in DNMT1. (Bashtrykov P, Jeltsch A. 2015.)

DNMT1 and Tumor

In recent years, a large number of studies have shown an association between cell cycle regulation and cancer and inhibition of cell cycle has become an appreciated target for the management of cancer. The study has shown that knockdown of DNMT1 can strongly inhibit the growth of human Endometrial carcinoma (EC) cells by the perturbation of G1-S phase transition. A recent study showed that DNMT1 protein interacted with β catenin and regulated Wnt signaling in colorectal cancer cells. CCND1 and CCND2 are the downstream targets of Wnt/β catenin signaling and the important effectors to enhance cell cycle progression. Thus, it is possible that the knockdown of DNMT1 decreased the stability and activity of β catenin and downregulated the expression of CCND1 and CCND2, resulting in cell cycle arrest. In addition, DNMT1 silencing has been shown to inhibit cell proliferation and alter cell cycle progression through cell cycle arrest and apoptosis in cervical cancer. DNMT1 inhibited the transcription of cell proliferation-related tumor suppressors, such as Bax and p27, which are associated with the development of several types of cancers.

Dnmt1 is essential for the maintenance of haematopoietic stem cells (HSCs)/progenitor cells, mesenchymal stem cells, epidermal progenitor cells and leukemia stem cells. Researchers showed that Dnmt1 is essential for mammary gland outgrowth and terminal end bud (TEB) development, and that mammary-gland-specific Dnmt1 deletion in mice results in significant reduction in mammary stem/progenitor cells. Besides, through genome-scale DNA methylation studies in normal and CSCs, they find ISL1, an endogenous inhibitor of oestrogen receptor (ER)-driven transcription activation, is hypermethylated in CSCs and silenced in most human breast cancers. Functional re-expression of ISL1 or inhibition of DNMT activity in breast cancer cells reduces cell growth, migration and CSC formation. These studies provide the first in vivo evidence showing a requirement for DNMT1 in mammary stem/progenitor cell and CSC maintenance, and identify DNMT1-ISL1 axis as a potential target for breast cancer treatment.

References:

Kah K W. DNMT1: A Key Drug Target in Triple-Negative Breast Cancer. Seminars in Cancer Biology. Academic Press, 2020.
Dhawan D, et al. DNMT1: an emerging target in the treatment of invasive urinary bladder cancer. Urologic Oncology: Seminars and Original Investigations. Elsevier, 2013, 31(8): 1761-1769.
Di Ruscio A, et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature, 2013, 503(7476): 371-376.
Bashtrykov P, Jeltsch A. DNMT1-associated DNA methylation changes in cancer. 2015.
Pathania R, et al. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nature communications, 2015, 6(1): 1-11.
Wang X, Li B. DNMT1 regulates human endometrial carcinoma cell proliferation. OncoTargets and therapy, 2017, 10: 1865.

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