​Sci Adv Jiemin Weng/Xuekun Li team work together to reveal the molecular mechanism of neurodegenerative diseases caused by DNMT1 mutations

Responsible editor | Zyme DNA methylation in mammals is an important epigenetic modification, which has the function of regulating gene activity, and plays an important role in embryonic development and nervous system development and differentiation [1-5]
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DNA methylation profile can be passed on to progeny cells during cell proliferation.
This is mainly due to the existence of maintenance DNA methylase 1 (DNMT1), which can remove parent strand DNA during DNA replication.
The basicization spectrum is copied to the sub-chain [6]
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Previous studies have found that heterozygous mutations in DNMT1 are hereditary sensory and autonomic neuropathy type 1E with dementia and hearing loss (HSAN1E) and autosomal dominant cerebellar coexistence.
Disorders, deafness and narcolepsy (autosomal dominant cerebellar ataxia, deafness, and narcolepsy, ADCA-DN) are the causes of two neurodegenerative diseases [7-9]
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Both diseases are manifested as autosomal dominant inheritance, with the characteristics of adult onset and age-dependent progression
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So far, all DNMT1 mutations found in HSAN1E and ADCA-DN patients are located in a specific domain (RFTS) of DNMT1, and HSAN1E mutations are located at the N-terminal or middle of RFTS, while ADCA-DN mutations are located at the C-terminal of RFTS
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However, how these mutations in the RFTS domain of DNMT1 affect the function of DNMT1 in vivo and therefore lead to neurodegenerative diseases is still unclear.

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Recently, the team of Professor Jiemin Weng of East China Normal University and the team of Professor Xuekun Li of Zhejiang University have made important progress in the pathogenic mechanism of HSAN1E.
The research results titled Mutation-induced DNMT1 cleavage drives neurodegenerative disease were published online in Science Advances on September 1, 2021.
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In this study, the team built two Dnmt1 mutant mouse models that mimic the common mutation sites of HSAN1E patients (Y500C mutant M1 mutant mice and P496Y mutant M2 mutant mice, which are equivalent to those found in human patients.
Y495C mutation and D490E-P491Y mutation), it was found that heterozygous mutant mice showed symptoms of neurodegeneration, and homozygous mutant mice were embryonic lethal
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In terms of molecular mechanism, the detection of mouse tissues and mouse embryonic stem (ES) cells, embryonic fibroblasts (MEF) cells, adult neural stem cells (aNSCs) and other cells found that the mutant DNMT1 protein is unstable, but not through the proteasome Or the lysosomal pathway, but because it is cleaved by a specific protease that has not yet been identified, and its cleavage products form protein aggregates in the nucleolus
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In order to study the effect of mutations on human DNMT1 protein, the team used single-base editing technology to construct cells with DNMT1 Y495C point mutations in two different types of human cell lines
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Further studies have shown that the protein of mutant DNMT1 is stable in HeLa cells that do not express specific proteases, and the cell location and enzyme activity are not significantly changed compared with wild-type DNMT1
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However, in human glial cells with specific protease expression, the mutant DNMT1 is cleaved, resulting in the accumulation of DNMT1 cleavage products in the nucleolus, abnormal DNA methylation, inhibition of cell proliferation, and apoptosis
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These findings indicate that the degradation of DNMT1 caused by the RFTS mutation, rather than the mutation itself, leads to the functional defect of the DNMT1 mutant
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Based on the fact that only missense mutations in the RFTS region are found in patients with the above two neurodegenerative diseases, but no nonsense mutations in this region and other regions are found, the author proposes to cause the above neurodegeneration The cause of the disease is, on the one hand, that the specific cleavage of the mutant DNMT1 protein leads to defects in its DNA methylation activity, on the other hand, the abnormal localization of the corresponding truncated nucleolus interferes with the normal function of the nucleolus (such as ribosomal RNA).
Transcription), which may eventually lead to defects in the development and differentiation of some nerve cells and apoptosis, leading to related neurodegenerative diseases
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The corresponding authors of this paper are Professor Weng Jiemin of East China Normal University and Professor Li Xuekun of Zhejiang University
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The first authors are Dr.
Wensi Wang from East China Normal University and Dr.
Xingsen Zhao from Zhejiang University.
This work was greatly helped by Professor Li Dali from East China Normal University and Professor Zhu Bing from the Institute of Biophysics, Chinese Academy of Sciences
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