Quick Search:

uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive 

Cortázar, D; Kunz, C; Selfridge, J; Lettieri, T; Saito, Y; Macdougall, E; Wirz, A; Schuermann, D; Jacobs, A L; Siegrist, F; Steinacher, R; Jiricny, J; Bird, A; Schär, P (2011). Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature, 470(7334):419-423.

Full text not available from this repository.

Abstract

Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5-methylcytosine (5-mC) deamination in mammalian DNA. However, TDG was also found to interact with transcription factors, histone acetyltransferases and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
DDC:570 Life sciences; biology
Language:English
Date:2011
Deposited On:08 Mar 2011 16:47
Last Modified:27 Nov 2013 18:36
Publisher:Nature Publishing Group
ISSN:0028-0836
Publisher DOI:10.1038/nature09672
PubMed ID:21278727
Citations:Web of Science®. Times Cited: 102
Google Scholar™
Scopus®. Citation Count: 109

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page