ArticleHuman molecular genetics2017
DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
- Article
- Disease-Associated Mutations Impact DNA Methyltransferase 1 Function through Dynamic Allosteric Effects and Solvent Exposure.Journal of chemical theory and computation · 2026Article
- Recent Advances in Searching for DNMT Inhibitors and Their Potential Application in Treating Human Diseases.International journal of molecular sciences · 2026Review
- Functional and Epigenomic Consequences ofInternational journal of molecular sciences · 2026Article
- Structure of human DPPA3 bound to the UHRF1 PHD finger reveals its functional and structural differences from mouse DPPA3.Communications biology · 2024Article
- Article
- Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1.Molecules (Basel, Switzerland) · 2023Review
- Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery.eLife · 2023Article
- UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats.Open medicine (Warsaw, Poland) · 2023Article
- Regulatory mechanism and biological function of UHRF1-DNMT1-mediated DNA methylation.Functional & integrative genomics · 2022Review
- Structural basis for the unique multifaceted interaction of DPPA3 with the UHRF1 PHD finger.Nucleic acids research · 2022Article
- Mutation-induced DNMT1 cleavage drives neurodegenerative disease.Science advances · 2021Article
- Insights into Conformational Dynamics and Allostery in DNMT1-H3Ub/USP7 Interactions.Molecules (Basel, Switzerland) · 2021Article
- Losing DNA methylation at repetitive elements and breaking bad.Epigenetics & chromatin · 2021Review
- Staying true to yourself: mechanisms of DNA methylation maintenance in mammals.Nucleic acids research · 2021Review
- Review
- DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism.Human molecular genetics · 2020Article
- dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye.Scientific reports · 2020Article
- Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAiScience · 2019Article
- Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DNMT1 is recruited to substrate sites by PCNA and UHRF1 to maintain DNA methylation after replication. The cell cycle dependent recruitment of DNMT1 is mediated by the PCNA-binding domain (PBD) and the targeting sequence (TS) within the N-terminal regulatory domain. The TS domain was found to be mutated in patients suffering from hereditary sensory and autonomic neuropathies with dementia and hearing loss (HSANIE) and autosomal dominant cerebellar ataxia deafness and narcolepsy (ADCA-DN) and is associated with global hypomethylation and site specific hypermethylation. With functional complementation assays in mouse embryonic stem cells, we showed that DNMT1 mutations P496Y and Y500C identified in HSANIE patients not only impair DNMT1 heterochromatin association, but also UHRF1 interaction resulting in hypomethylation. Similar DNA methylation defects were observed when DNMT1 interacting domains in UHRF1, the UBL and the SRA domain, were deleted. With cell-based assays, we could show that HSANIE associated mutations perturb DNMT1 heterochromatin association and catalytic complex formation at methylation sites and decrease protein stability in late S and G2 phase. To investigate the neuronal phenotype of HSANIE mutations, we performed DNMT1 rescue assays and could show that cells expressing mutated DNMT1 were prone to apoptosis and failed to differentiate into neuronal lineage. Our results provide insights into the molecular basis of DNMT1 dysfunction in HSANIE patients and emphasize the importance of the TS domain in the regulation of DNA methylation in pluripotent and differentiating cells.
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