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PMID: 15899845 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The thymine DNA glycosylase MBD4 represses transcription and is associated with methylated p16(INK4a) and hMLH1 genes.

Molecular and cellular biology ·Vol. 25 ·No. 11 ·2005-06-00 ·Pages 4388-96

Kondo E, Gu Z, Horii A, Fukushige S

Abstract

Epigenetic silencing through methyl-CpG (mCpG) is implicated in many biological patterns such as genome imprinting, X chromosome inactivation, and cancer development. In this process, the mCpG binding domain (MBD) proteins play an essential role in transmitting epigenetic information to downstream regulatory proteins. Among the five MBD proteins identified so far, MBD4 has been the only exception; it has long been thought to be a DNA repair protein. Herein we demonstrate that MBD4 has the ability to repress transcription through mCpG. Transcriptional repression by the MBD4 is histone deacetylase (HDAC) dependent, and MBD4 directly binds to Sin3A and HDAC1 at three central regions that overlap transcriptional repression domains. Furthermore, a chromatin immunoprecipitation assay clearly shows that MBD4 binds to hypermethylated promoters of the p16(INK4a) and hMLH1 genes. These results suggest that MBD4 is one of the essential components involved in epigenetic silencing in cancer and its repair activity is necessary for the maintenance of hypermethylated promoters.

MeSH Terms
Adaptor Proteins, Signal Transducing Carrier Proteins Cells, Cultured Chromatin Immunoprecipitation CpG Islands Cyclin-Dependent Kinase Inhibitor p16/genetics DNA Methylation Endodeoxyribonucleases/genetics,metabolism Epigenesis, Genetic Gene Silencing Histone Deacetylase 1 Histone Deacetylases/metabolism Humans MutL Protein Homolog 1 Neoplasm Proteins/genetics Nuclear Proteins/genetics Promoter Regions, Genetic Protein Interaction Mapping Repressor Proteins/genetics,metabolism Sin3 Histone Deacetylase and Corepressor Complex Thymine DNA Glycosylase/genetics,metabolism Transcription, Genetic
Chemicals
Adaptor Proteins, Signal Transducing Carrier Proteins Cyclin-Dependent Kinase Inhibitor p16 MLH1 protein, human Neoplasm Proteins Nuclear Proteins Repressor Proteins SIN3A transcription factor Endodeoxyribonucleases MBD4 protein, human Thymine DNA Glycosylase HDAC1 protein, human Histone Deacetylase 1 Histone Deacetylases Sin3 Histone Deacetylase and Corepressor Complex MutL Protein Homolog 1
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Kondo Emiko
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Gu Zhaodi
Horii Akira
Fukushige Shinichi
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.11.4388-4396.2005
Published
2005-06-00
Pages
4388-96
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1140624
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.25.11.4388-4396.2005 PMC Full Text View journal details
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