Other Name(s): DNMT
Drug Target Analysis Report Drug Target Analysis Report Content

About the Target

Based on the provided context information, here are the key viewpoints related to DNMT1:

In CML cells, phosphorylation of beta-catenin by BCR-ABL1 leads to stabilization of beta-catenin and its translocation into the nucleus, where it acts as a transcriptional activator for many genes, including DNMT1. This results in the down-regulation of PTPRG, as DNMT1 is responsible for PTPRG promoter methylation and subsequent down-regulation [1].

PTPRG, a tumor suppressor, plays a role in the degradation of beta-catenin. It dephosphorylates BCR-ABL1, preventing beta-catenin tyrosine phosphorylation. PTPRG also directly dephosphorylates beta-catenin, leading to its proteolysis. This condition affects the transcription of DNMT1, causing its down-regulation and hypomethylation of the PTPRG promoter region [1].

In SALL2-hypermethylated ER+ breast cancer, the reduction of SALL2 due to promoter methylation represses the expression of ERalpha and PTEN while activating Akt/mTOR signaling. This results in estrogen-independent tumor growth and tamoxifen resistance. Restoring SALL2 expression using a DNMT inhibitor resensitizes tamoxifen-resistant breast cancer to endocrine therapy [2].

A regulatory circuit involving miR-148a/DNMT1/OCT4/autophagy is speculated to exist in WJ-MSCs. This circuit may be differently modulated based on gender [3].

During osteogenic differentiation of AF-MSCs, chromatin regions undergo remodeling through epigenetic changes. Histone modifications and changes in the expression of enzymes such as DNMT1 play a crucial role in this process. Epigenetic changes are important for the osteogenic differentiation of AF-MSCs [4].

In relation to KRAS activation, DNMT1 is not directly driven by KRAS but instead, KRAS induces miR-29 through the RAF-MEK-ERK pathway. Net hypermethylation depends on the down-regulation of TET1. TET1 and DNMT1 are both present on target gene promoters prior to KRAS activation [5].

These viewpoints provide insights into the role of DNMT1 in various biological processes and diseases, such as CML, breast cancer, differentiation of mesenchymal stem cells, and the regulation of gene expression by KRAS.
Based on the provided context information, the key viewpoints related to DNMT1 are:

DNMT1 plays a role in silencing DNA regions after replication by catalyzing the addition of repressive histone marks (H3K9me3), removal of H3 acetylation, and methylation of the new DNA strand [6].
The complex involving DNMT1, UHRF1, PCNA, G9a, and HDAC1 is responsible for this silencing process [6].
DNMT1 also contributes to de novo methylation of specific DNA regions, such as heterochromatin (e.g., major satellites), along with the recruitment of DNMT3A and/or DNMT3B [6].
The repressive histone mark H3K9me3, added by SUV39H1, is read by HP1, which then recruits DNMT3A and/or DNMT3B for DNA methylation [6].

These viewpoints highlight the cooperation between DNMT1 and various proteins involved in post-translational modifications of histones for both silencing DNA after replication and de novo methylation of specific DNA regions. Additionally, HP1 plays a crucial role in recruiting DNMT3A and/or DNMT3B for DNA methylation [6].

Figure [1]

Figure [2]

Figure [3]

Figure [4]

Figure [5]

Figure [6]

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