Accession |
PRJCA012035 |
Title |
Mutation-induced DNMT1 cleavage drives neurodegenerative disease |
Relevance |
Medical |
Data types |
Transcriptome or Gene expression
Raw sequence reads
|
Organisms |
Mus musculus
|
Description |
Specific mutations within the replication foci targeting sequence (RFTS) domain of human DNMT1 are causative of two types of adult-onset neurodegenerative diseases, HSAN1E and ADCA-DN, but the underlying mechanisms are largely unknown. We generated Dnmt1-M1 and Dnmt1-M2 knock-in mouse models that are equivalent to Y495C and D490E-P491Y mutation in patients with HSAN1E, respectively. We found that both mutant heterozygous mice are viable, have reduced DNMT1 proteins, and exhibit neurodegenerative phenotypes including impaired learning and memory. The homozygous mutants die around embryonic day 10.5 and are apparently devoid of DNMT1 proteins. We present the evidence that the mutant DNMT1 proteins are unstable, most likely because of cleavage within RFTS domain by an unidentified proteinase. Moreover, we provide evidence that the RFTS mutation-induced cleavage of DNMT1, but not mutation itself, is responsible for functional defect of mutant DNMT1. Our study shed light on the mechanism of DNMT1 RFTS mutation causing neurodegenerative diseases. |
Sample scope |
Multiisolate |
Release date |
2022-09-21 |
Publication |
|
Grants |
Agency |
program |
Grant ID |
Grant title |
Ministry of Science and Technology of the People's Republic of China (MOST)
|
|
2017YFA0504200
|
|
National Natural Science Foundation of China (NSFC)
|
|
31730048
|
|
National Natural Science Foundation of China (NSFC)
|
|
81530078
|
|
National Natural Science Foundation of China (NSFC)
|
|
31771395
|
|
National Natural Science Foundation of China (NSFC)
|
|
31900453
|
|
National Key Research and Development Program of China
|
|
2017YFE0196600
|
|
|
Submitter |
Jiemin
Wong (jmweng@bio.ecnu.edu.cn)
|
Organization |
East China Normal University |
Submission date |
2022-09-21 |