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Title: ATRX ADD Domain Links an Atypical Histone Methylation Recognition Mechanism to Human Mental-Retardation Syndrome

Abstract

ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD{sub ATRX}), whose function has remained elusive. Here we identify ADD{sub ATRX} as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD{sub ATRX} bound to H3{sub 1-15}K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1041959
Report Number(s):
BNL-97637-2012-JA
Journal ID: ISSN 1545-9993; TRN: US201212%%370
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Nature Structural and Molecular Biology
Additional Journal Information:
Journal Volume: 18; Journal Issue: 7; Journal ID: ISSN 1545-9993
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AROMATICS; ETIOLOGY; HETEROCHROMATIN; HISTONES; LYSINE; METHYLATION; MUTANTS; MUTATIONS; PEPTIDES

Citation Formats

Iwase, S, Xiang, B, Ghosh, S, Ren, T, Lewis, P, Cochrane, J, Allis, C, Picketts, D, Patel, D, and et al. ATRX ADD Domain Links an Atypical Histone Methylation Recognition Mechanism to Human Mental-Retardation Syndrome. United States: N. p., 2011. Web. doi:10.1038/nsmb.2062.
Iwase, S, Xiang, B, Ghosh, S, Ren, T, Lewis, P, Cochrane, J, Allis, C, Picketts, D, Patel, D, & et al. ATRX ADD Domain Links an Atypical Histone Methylation Recognition Mechanism to Human Mental-Retardation Syndrome. United States. https://doi.org/10.1038/nsmb.2062
Iwase, S, Xiang, B, Ghosh, S, Ren, T, Lewis, P, Cochrane, J, Allis, C, Picketts, D, Patel, D, and et al. 2011. "ATRX ADD Domain Links an Atypical Histone Methylation Recognition Mechanism to Human Mental-Retardation Syndrome". United States. https://doi.org/10.1038/nsmb.2062.
@article{osti_1041959,
title = {ATRX ADD Domain Links an Atypical Histone Methylation Recognition Mechanism to Human Mental-Retardation Syndrome},
author = {Iwase, S and Xiang, B and Ghosh, S and Ren, T and Lewis, P and Cochrane, J and Allis, C and Picketts, D and Patel, D and et al.},
abstractNote = {ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD{sub ATRX}), whose function has remained elusive. Here we identify ADD{sub ATRX} as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD{sub ATRX} bound to H3{sub 1-15}K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.},
doi = {10.1038/nsmb.2062},
url = {https://www.osti.gov/biblio/1041959}, journal = {Nature Structural and Molecular Biology},
issn = {1545-9993},
number = 7,
volume = 18,
place = {United States},
year = {Sat Dec 31 00:00:00 EST 2011},
month = {Sat Dec 31 00:00:00 EST 2011}
}