Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation.
Mutations in the human methyl-CpG-binding protein gene MECP2 cause the neurological disorder Rett syndrome and some cases of X-linked mental retardation (XLMR). We report that MeCP2 interacts with ATRX, a SWI2/SNF2 DNA helicase/ATPase that is mutated in ATRX syndrome (alpha-thalassemia/mental retardation, X-linked). MeCP2 can recruit the helicase domain of ATRX to heterochromatic foci in living mouse cells in a DNA methylation-dependent manner. Also, ATRX localization is disrupted in neurons of Mecp2-null mice. Point mutations within the methylated DNA-binding domain of MeCP2 that cause Rett syndrome or X-linked mental retardation inhibit its interaction with ATRX in vitro and its localization in vivo without affecting methyl-CpG binding. We propose that disruption of the MeCP2-ATRX interaction leads to pathological changes that contribute to mental retardation.
Nan
Xinsheng
X
Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, United Kingdom. xinsheng.nan@csc.mrc.ac.uk
Hou
Jianghui
J
Maclean
Alan
A
Nasir
Jamal
J
Lafuente
Maria Jose
MJ
Shu
Xinhua
X
Kriaucionis
Skirmantas
S
Bird
Adrian
A
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D020798:Two-Hybrid System Techniques; D000075924:X-linked Nuclear Protein
D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins; D004247:DNA; D004265:DNA Helicases; C092332:ATRX protein, human; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein