DNMT1 and Associated Diseases
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Backgrounds of DNMT1 Gene
DNMT1, the major DNA methyltransferase in mammalian cells, is a large, highly dynamic enzyme with multiple regulatory properties that control intracellular DNA methylation. Allosteric sites on DNMT1 regulate the process of de novo DNA synthesis and maintain DNA methylation in cells. DNMT1 consists of a large regulatory N-terminal region and a smaller catalytic C-terminal region.
Fig.1 Schematic representation of (A) the structure of the DNMT1 gene and (B) the process of DNA methylation. (Algahtani, 2017)
Functions of DNMT1
DNMT1 is the only essential component that maintains methyltransferases and cellular epigenetic regulation. It plays an integral role during embryonic development and is crucial in chromatin structure, neuronal survival, and cell cycle regulation. The primary function of DNMT1 is to maintain and stabilize gene methylation. Protective effects of plastrum testudinis extract on dopaminergic neurons in a Parkinson's disease (PD) model through DNMT1 nuclear translocation and SNCA methylation. Growing evidence has implicated the roles and significance of DNMT1 in pancreatic cancer tumorigenesis, aggressiveness, and response to treatment. DNMT1 is essential for DNA methylation, gene regulation, and chromatin stability. DNMT1 is indispensable for cell development, cell function, and cell cycle regulation. Genomic deletion of DNMT1 in mice leads to embryonic death, and complete deletion of DNMT1 in human cancer cells results in significant loss of global methylation, pronounced chromosomal defects, and apoptosis.
Association of DNMT1 Expression With Diseases
Autosomal dominant heterozygous mutations in DNMT1 have recently been identified as the cause of two neurodegenerative disorders characterized by adult onset and age-dependent progression :(i) hereditary sensory autonomic neuropathy with dementia and hearing loss, and (ii) cerebellar ataxia, deafness, and narcolepsy. Loss of DNMT1 eventually leads to a decrease in the methylation level of Snca, which in turn leads to an increase in α-synuclein expression. This may be an important pathological feature in the development of PD. Loss of DNMT1 can also delay the development of lymphoma by inhibiting normal hematopoiesis and impairing tumor proliferation. The expression of DNMT1 in the GATA-4 promoter region was also upregulated in the hearts of vitamin-deficient offspring, and the incidence of heart defects was higher in vitamin-A-deficient offspring. DNMT1 mutants appear to exert their destructive effects via two complex pathways.
- The misfolded mutant DNMT1 stresses the cell by throwing the protein homeostasis network out of balance, which may ultimately lead to cell death.
- Epigenetic pathways are impaired, resulting in aberrant global methylation in HSAN1E patients.
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Reference
- Algahtani, H.; Shirah, B. A novel mutation in the DNMT1 gene in a patient presenting with pure cerebellar ataxia. Journal of Genetic Medicine. 2017, 14(2): 71-74.
