Download Gene Section MBD2 (methyl CpG binding domain protein 2)

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MBD2 (methyl CpG binding domain protein 2)
Heather Owen
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, King's
Buildings, Mayfield Road, Edinburgh EH9 3JR, UK (HO)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/MBD2ID41309ch18q21.html
DOI: 10.4267/2042/44826
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
The shorter transcript NM_015832.3, mRNA length of
1357 bp is expressed in germ cells (according to
symatlas).
Identity
Other
names:
DKFZp586O0821;
Demethylase; NY-CO-41
HGNC (Hugo): MBD2
Location: 18q21.2
Note: Homologous to MBD3 gene.
DMTase;
Protein
Description
In somatic tissues MBD2 is expressed from a single
transcript, and is detected by western blot as 2 stable
proteins at approximately 50 kDa (MBD2a) and 30 kDa
(MBD2b). Human MBD2a (Q9UBB5) has 411 amino
acids. It is unknown whether MBD2b is due to use of
an alternative translation start site (creating protein of
262
amino
acids)
or
due
to
protein
cleavage/processing/degradation.
Human germ cells express a short form of MBD2 from
the alternative transcript with an expected length of 302
amino acids.
DNA/RNA
Description
MBD2 (NM_003927.3) is a gene of 70,583 bp coded
by 7 exons from 33,240,260 to 33,169,677 according to
NCBI reference sequence NT_010966.14 or
51,751,158 to 51,680,575 according to Genome
reference consortium human build 37 GRCh37. There
is an alternative transcript for MBD2 (NM_015832.3)
of 22,111 bp from 33,240,260 to 33,218,149 on NCBI
reference sequence NT_010966.14. This transcript
shares the first 2 exons (coding for the methyl binding
domain) but differs in the 3rd exon, resulting in a
shorter truncated protein.
Expression
MBD2a and MBD2b are expressed in all tissues tested
with highest levels in spleen and colon nuclei (nonpublished observation).
Transcription
Localisation
The longer transcript encoded by NM_003927.3,
mRNA length of 2584 bp, is expressed ubiquitiously
(according to symatlas).
MBD2 is a nuclear protein. MBD2-GFP localises to
major satellite in mouse ES cells, but not in DNA
methylation deficient cells (Hendrich and Bird, 1998).
MBD2 is expressed as 2 transcripts. NM_003927.3 coding sequence in blue and NM_015832.3 in red. Boxes represent exons and
arrows represent transcriptional start sites.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
768
MBD2 (methyl CpG binding domain protein 2)
Owen H
MBD: methyl binding domain, P: phosphorylation detected.
have been reported. However the global genomic
targets of MBD2 have not been characterised. MBD2
knock out are viable and fertile, and show only mild
physiological defects. These are abnormal maternal
behaviour and T helper cell deficiencies (Hendrich,
2001; Hutchins, 2002; Hutchins, 2005).
Function
MBD2 is a methyl binding protein that is thought to
repress gene expression as part of the NuRD complex.
The NuRD complex was identified independently by
four separate groups (Wade et al., 1998; Tong et al.,
1998; Xue et al., 1998; Zhang et al., 1998). NuRD
consists of a chromatin remodelling ATPase Mi2alpha
or beta, histone deacetylase HDAC1/HDAC2, MTA1
or MTA2, RbAp46/RbAp48, p66alpha/beta and can
also contain MBD2 or MBD3. TAP tagged MBD2a
associates with NuRD with equimolar stoichometry
implying that most MBD2a is complexed with NuRD
in cells (Le Guezennec et al., 2006). MBD2 is required
for repression of methylated reporter genes (Hendrich,
2001) and many endogenous target genes of MBD2
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
Homology
MBD2 is a member of the methyl-binding domain
proteins (Hendrich and Bird, 1998). Other members of
this family are MeCp2, MBD2, MBD3 and MBD4
(Klose and Bird, 2006). These proteins share a region
of homology (145-213 of MBD2a), which have been
shown to form a stable domain consisting of a beta
sheet, an alpha helix and a positioned loop (Ohki et al.,
2001). The crystal structure of the MBD of MeCP2
769
MBD2 (methyl CpG binding domain protein 2)
Owen H
complexed with a methylated CpG containing 20mer of
DNA indicates that the protein-DNA interactions are
dependent on water molecules (Ho et al., 2008). The
protein with closest homology to MBD2 is MBD3,
however MBD3 has two crucial amino acid
substitutions in the MBD and does not specifically bind
to methylated DNA (Hendrich and Tweedie, 2003).
Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber
SL. Chromatin deacetylation by an ATP-dependent
nucleosome remodelling complex. Nature. 1998 Oct
29;395(6705):917-21
Mutations
Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W.
NURD, a novel complex with both ATP-dependent chromatinremodeling and histone deacetylase activities. Mol Cell. 1998
Dec;2(6):851-61
Wade PA, Jones PL, Vermaak D, Wolffe AP. A multiple subunit
Mi-2 histone deacetylase from Xenopus laevis cofractionates
with an associated Snf2 superfamily ATPase. Curr Biol. 1998
Jul 2;8(14):843-6
Note
MBD2 is mutated only infrequently in human cancer
tissues.
Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D. The
dermatomyositis-specific autoantigen Mi2 is a component of a
complex containing histone deacetylase and nucleosome
remodeling activities. Cell. 1998 Oct 16;95(2):279-89
Implicated in
Hendrich B, Abbott C, McQueen H, Chambers D, Cross S, Bird
A. Genomic structure and chromosomal mapping of the murine
and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm
Genome. 1999 Sep;10(9):906-12
Intestinal tumorigenesis
Note
MBD2-/- APCmin/+ mice have fewer intestinal tumors
and survive longer than MBD2+/+ APCmin/+ mice
(Sansom, 2003).
These results imply MBD2 is required for
tumorigenesis. Although the mechanism is unknown,
possibilities are listed below:
1) MBD2 may repress tumor supressor genes (therefore
in the absence of MBD2, tumor repressor expression
would be upregulated). In cancer cell lines MBD2 has
been found to bind to methylated regions of tumor
supressor genes GSTP1, p14 and p16 (Stirzaker, 2004;
Le Guezennec, 2006; Martin, 2008).
2) MBD2 may repress a repressor of WNT signalling
(therefore in the absence of MBD2, WNT signalling
would be reduced). One candidate for this is Lect2
(Phesse, 2008).
3) In mice MBD2 is required for normal T cell
differentiation and MBD2-/- mice have impaired
immune responses. This could contribute to the MBD2
requirement in tumor formation in the APCmin/+ strain
(Hutchins, 2002; Hutchins, 2005).
4) Other mechanisms are possible, such as a role of
mbd2 in higher order chromatin or silencing of
heterochromatin regulating tumorigenesis. However
this has not been tested.
Knock down of MBD2 in human cancer cell lines
reduced tumor volume when implanted into nude mice
(Campbell, 2004).
MBD2 expression levels in human cancer tissues have
been analysed in multiple studies with differing results.
One study found MBD2 expression was low in
colorectal and stomach cancers (Kanai, 1999), whereas
other studies found high expression in cancer tissues.
These discrepancies are likely due to differences
between control genes used as well as differences
between cancer tissues.
Kanai Y, Ushijima S, Nakanishi Y, Hirohashi S. Reduced
mRNA expression of the DNA demethylase, MBD2, in human
colorectal and stomach cancers. Biochem Biophys Res
Commun. 1999 Nov 2;264(3):962-6
Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM,
Erdjument-Bromage H, Tempst P, Reinberg D, Bird A. MBD2
is a transcriptional repressor belonging to the MeCP1 histone
deacetylase complex. Nat Genet. 1999 Sep;23(1):58-61
Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A. Closely
related proteins MBD2 and MBD3 play distinctive but
interacting roles in mouse development. Genes Dev. 2001 Mar
15;15(6):710-23
Ohki I, Shimotake N, Fujita N, Jee J, Ikegami T, Nakao M,
Shirakawa M. Solution structure of the methyl-CpG binding
domain of human MBD1 in complex with methylated DNA.
Cell. 2001 May 18;105(4):487-97
Hutchins AS, Mullen AC, Lee HW, Sykes KJ, High FA,
Hendrich BD, Bird AP, Reiner SL. Gene silencing quantitatively
controls the function of a developmental trans-activator. Mol
Cell. 2002 Jul;10(1):81-91
Bader S, Walker M, McQueen HA, Sellar R, Oei E, Wopereis
S, Zhu Y, Peter A, Bird AP, Harrison DJ. MBD1, MBD2 and
CGBP genes at chromosome 18q21 are infrequently mutated
in human colon and lung cancers. Oncogene. 2003 May
29;22(22):3506-10
Hendrich B, Tweedie S. The methyl-CpG binding domain and
the evolving role of DNA methylation in animals. Trends Genet.
2003 May;19(5):269-77
Lin X, Nelson WG. Methyl-CpG-binding domain protein-2
mediates
transcriptional
repression
associated
with
hypermethylated GSTP1 CpG islands in MCF-7 breast cancer
cells. Cancer Res. 2003 Jan 15;63(2):498-504
Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A, Clarke
AR. Deficiency of Mbd2 suppresses intestinal tumorigenesis.
Nat Genet. 2003 Jun;34(2):145-7
Campbell PM, Bovenzi V, Szyf M. Methylated DNA-binding
protein 2 antisense inhibitors suppress tumourigenesis of
human cancer cell lines in vitro and in vivo. Carcinogenesis.
2004 Apr;25(4):499-507
References
Stirzaker C, Song JZ, Davidson B, Clark SJ. Transcriptional
gene silencing promotes DNA hypermethylation through a
sequential change in chromatin modifications in cancer cells.
Cancer Res. 2004 Jun 1;64(11):3871-7
Hendrich B, Bird A. Identification and characterization of a
family of mammalian methyl-CpG binding proteins. Mol Cell
Biol. 1998 Nov;18(11):6538-47
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
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MBD2 (methyl CpG binding domain protein 2)
Owen H
Berger J, Bird A. Role of MBD2 in gene regulation and
tumorigenesis. Biochem Soc Trans. 2005 Dec;33(Pt 6):153740
Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP,
Walkinshaw MD. MeCP2 binding to DNA depends upon
hydration at methyl-CpG. Mol Cell. 2008 Feb 29;29(4):525-31
Hutchins AS, Artis D, Hendrich BD, Bird AP, Scott P, Reiner
SL. Cutting edge: a critical role for gene silencing in preventing
excessive type 1 immunity. J Immunol. 2005 Nov
1;175(9):5606-10
Martin V, Jørgensen HF, Chaubert AS, Berger J, Barr H, Shaw
P, Bird A, Chaubert P. MBD2-mediated transcriptional
repression of the p14ARF tumor suppressor gene in human
colon cancer cells. Pathobiology. 2008;75(5):281-7
Klose RJ, Bird AP. Genomic DNA methylation: the mark and its
mediators. Trends Biochem Sci. 2006 Feb;31(2):89-97
Phesse TJ, Parry L, Reed KR, Ewan KB, Dale TC, Sansom
OJ, Clarke AR. Deficiency of Mbd2 attenuates Wnt signaling.
Mol Cell Biol. 2008 Oct;28(19):6094-103
Le Guezennec X, Vermeulen M, Brinkman AB, Hoeijmakers
WA, Cohen A, Lasonder E, Stunnenberg HG. MBD2/NuRD
and MBD3/NuRD, two distinct complexes with different
biochemical and functional properties. Mol Cell Biol. 2006
Feb;26(3):843-51
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
This article should be referenced as such:
Owen H. MBD2 (methyl CpG binding domain protein 2). Atlas
Genet Cytogenet Oncol Haematol. 2010; 14(8):768-771.
771