The thymine DNA glycosylase MBD4 represses transcription and is associated with methylated p16INK4a and hMLH1 genes

被引：87

作者：

Kondo, E ^{[1
]}

Gu, ZD ^{[1
]}

Horii, A ^{[1
]}

Fukushige, S ^{[1
]}

机构：

[1] Tohoku Univ, Sch Med, Dept Mol Pathol, Aoba Ku, Sendai, Miyagi 9808575, Japan

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2005年 / 25卷 / 11期

关键词：

D O I：

10.1128/MCB.25.11.4388-4396.2005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4388 / 4396

页数：9

共 37 条

[1] Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression [J].

Alland, L ;

Muhle, R ;

Hou, H ;

Potes, J ;

Chin, L ;

SchreiberAgus, N ;

DePinho, RA .

NATURE, 1997, 387 (6628) :49-55

[2] Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene [J].

Bachman, KE ;

Park, BH ;

Rhee, I ;

Rajagopalan, H ;

Herman, JG ;

Baylin, SB ;

Kinzler, KW ;

Vogelstein, B .

CANCER CELL, 2003, 3 (01) :89-95

[3] Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency [J].

Bader, S ;

Walker, M ;

Heindrich, B ;

Bird, A ;

Bird, C ;

Hooper, M ;

Wyllie, A .

ONCOGENE, 1999, 18 (56) :8044-8047

[4] Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer [J].

Ballestar, E ;

Paz, MF ;

Valle, L ;

Wei, S ;

Fraga, MF ;

Espada, J ;

Cigudosa, JC ;

Huang, THM ;

Esteller, M .

EMBO JOURNAL, 2003, 22 (23) :6335-6345

[5] Methyl-CpG-binding proteins - Targeting specific gene repression [J].

Ballestar, E ;

Wolffe, AP .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (01) :1-6

[6] MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1 [J].

Bellacosa, A ;

Cicchillitti, L ;

Schepis, F ;

Riccio, A ;

Yeung, AT ;

Matsumoto, Y ;

Golemis, EA ;

Genuardi, M ;

Neri, G .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (07) :3969-3974

[7] DEMETER, a DNA glycosylase domain protein, is required for endosperm gene imprinting and seed viability in Arabidopsis [J].

Choi, YH ;

Gehring, M ;

Johnson, L ;

Hannon, M ;

Harada, JJ ;

Goldberg, RB ;

Jacobsen, SE ;

Fischer, RL .

CELL, 2002, 110 (01) :33-42

[8] The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity [J].

Cortellino, S ;

Turner, D ;

Masciullo, V ;

Schepis, F ;

Albino, D ;

Daniel, R ;

Skalka, AM ;

Meropol, NJ ;

Alberti, C ;

Larue, L ;

Bellacosa, A .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (25) :15071-15076

[9] GENOMIC TARGETING WITH A POSITIVE-SELECTION LOX INTEGRATION VECTOR ALLOWS HIGHLY REPRODUCIBLE GENE-EXPRESSION IN MAMMALIAN-CELLS [J].

FUKUSHIGE, S ;

SAUER, B .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (17) :7905-7909

[10] A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression [J].

Heinzel, T ;

Lavinsky, RM ;

Mullen, TM ;

Soderstrom, M ;

Laherty, CD ;

Torchia, J ;

Yang, WM ;

Brard, G ;

Ngo, SD ;

Davie, JR ;

Seto, E ;

Eisenman, RN ;

Rose, DW ;

Glass, CK ;

Rosenfeld, MG .

NATURE, 1997, 387 (6628) :43-48

← 1 2 3 4 →