ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner

Martin J. Law, Karen M. Lower, Hsiao P J Voon, Jim R Hughes, David Garrick, Vip Viprakasit, Matthew Mitson, Marco De Gobbi, Marco Marra, Andrew Morris, Aaron Abbott, Steven P. Wilder, Stephen Taylor, Guilherme M. Santos, Joe Cross, Helena Ayyub, Steven Jones, Jiannis Ragoussis, Daniela Rhodes, Ian DunhamDouglas R. Higgs, Richard J Gibbons

Research output: Contribution to journalArticleResearchpeer-review

248 Citations (Scopus)

Abstract

ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRX is mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRX mutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated.

Original languageEnglish
Pages (from-to)367-378
Number of pages12
JournalCell
Volume143
Issue number3
DOIs
Publication statusPublished - 29 Oct 2010
Externally publishedYes

Keywords

  • DNA
  • HUMDISEASE
  • PROTEINS

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