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PMID: 20110566 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells.

Genome research ·Vol. 20 ·No. 3 ·2010-03-00 ·Pages 351-60

Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, George AJ, Morgan KA, Mann JR, Choo KH

Abstract

ATRX (alpha thalassemia/mental retardation syndrome X-linked) belongs to the SWI2/SNF2 family of chromatin remodeling proteins. Besides the ATPase/helicase domain at its C terminus, it contains a PHD-like zinc finger at the N terminus. Mutations in the ATRX gene are associated with X-linked mental retardation (XLMR) often accompanied by alpha thalassemia (ATRX syndrome). Although ATRX has been postulated to be a transcriptional regulator, its precise roles remain undefined. We demonstrate ATRX localization at the telomeres in interphase mouse embryonic stem (ES) cells in synchrony with the incorporation of H3.3 during telomere replication at S phase. Moreover, we found that chromobox homolog 5 (CBX5) (also known as heterochromatin protein 1 alpha, or HP1 alpha) is also present at the telomeres in ES cells. We show by coimmunoprecipitation that this localization is dependent on the association of ATRX with histone H3.3, and that mutating the K4 residue of H3.3 significantly diminishes ATRX and H3.3 interaction. RNAi-knockdown of ATRX induces a telomere-dysfunction phenotype and significantly reduces CBX5 enrichment at the telomeres. These findings suggest a novel function of ATRX, working in conjunction with H3.3 and CBX5, as a key regulator of ES-cell telomere chromatin.

MeSH Terms
Adenosine Triphosphatases/chemistry Animals Chromatin/metabolism,physiology Chromatin Assembly and Disassembly Chromobox Protein Homolog 5 Chromosomal Proteins, Non-Histone/genetics,metabolism Chromosomes/metabolism DNA Helicases/genetics,metabolism DNA Replication/genetics,physiology Embryonic Stem Cells/metabolism Genes Histones/genetics,metabolism Humans Intellectual Disability/genetics Interphase/genetics Mental Retardation, X-Linked/genetics Mice Mutation Nuclear Proteins/genetics,metabolism Pluripotent Stem Cells/metabolism Telomere/metabolism X-linked Nuclear Protein alpha-Thalassemia/genetics
Chemicals
CBX5 protein, human CBX5 protein, mouse Chromatin Chromosomal Proteins, Non-Histone Histones Nuclear Proteins Chromobox Protein Homolog 5 Adenosine Triphosphatases DNA Helicases ATRX protein, human X-linked Nuclear Protein
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Wong Lee H
Chromosome and Chromatin Research, Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria 3052, Australia. lee.wong@mcri.edu.au
McGhie James D
Sim Marcus
Anderson Melissa A
Ahn Soyeon
Hannan Ross D
George Amee J
Morgan Kylie A
Mann Jeffrey R
Choo K H Andy
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1549-5469
DOI
10.1101/gr.101477.109
Email
lee.wong@mcri.edu.au
Published
2010-03-00
Epub
2010-00-28
Pages
351-60
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC2840985
Subset
IM
External Links
PubMed source DOI: 10.1101/gr.101477.109 PMC Full Text View journal details
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