English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation

Smets, M., Link, S., Wolf, P., Schneider, K., Solis, V., Ryan, J., et al. (2017). DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation. Human Molecular Genetics, 26(8), 1522-1534. doi:10.1093/hmg/ddx057.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-A5F1-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-A5F5-0
Genre: Journal Article

Files

show Files
hide Files
:
ddx057.pdf (Publisher version), 2MB
Name:
ddx057.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© The Author 2017. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).
License:
-
:
ddx057_Supp.docx (Supplementary material), 4MB
Name:
ddx057_Supp.docx
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/vnd.openxmlformats-officedocument.wordprocessingml.document / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© The Author 2017.
License:
-

Locators

show

Creators

show
hide
 Creators:
Smets, Martha1, Author
Link, Stephanie1, Author
Wolf, Patricia1, Author
Schneider, Katrin1, Author
Solis, Veronica2, Author              
Ryan, Joel1, Author
Meilinger, Daniela1, Author
Qin, Weihua1, Author
Leonhardt, Heinrich1, Author
Affiliations:
1external, ou_persistent22              
2Emeritus Group: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society, ou_1113547              

Content

show
hide
Free keywords: DNA METHYLTRANSFERASE 1; EMBRYONIC STEM-CELLS; HEMI-METHYLATED DNA; SRA DOMAIN; MAMMALIAN DEVELOPMENT; ADULT NEUROGENESIS; STRUCTURAL INSIGHT; CEREBELLAR-ATAXIA; GENE-EXPRESSION; PROTEIN UHRF1Biochemistry & Molecular Biology; Genetics & Heredity;
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2017-03-032017-04-15
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: ISI: 000400911900012
DOI: 10.1093/hmg/ddx057
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Human Molecular Genetics
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 26 (8) Sequence Number: - Start / End Page: 1522 - 1534 Identifier: ISSN: 0964-6906
CoNE: /journals/resource/954925581153