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

226 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

Cite this

Law, M. J., Lower, K. M., Voon, H. P. J., Hughes, J. R., Garrick, D., Viprakasit, V., ... Gibbons, R. J. (2010). ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell, 143(3), 367-378. https://doi.org/10.1016/j.cell.2010.09.023
Law, Martin J. ; Lower, Karen M. ; Voon, Hsiao P J ; Hughes, Jim R ; Garrick, David ; Viprakasit, Vip ; Mitson, Matthew ; Gobbi, Marco De ; Marra, Marco ; Morris, Andrew ; Abbott, Aaron ; Wilder, Steven P. ; Taylor, Stephen ; Santos, Guilherme M. ; Cross, Joe ; Ayyub, Helena ; Jones, Steven ; Ragoussis, Jiannis ; Rhodes, Daniela ; Dunham, Ian ; Higgs, Douglas R. ; Gibbons, Richard J. / ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. In: Cell. 2010 ; Vol. 143, No. 3. pp. 367-378.
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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.",
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author = "Law, {Martin J.} and Lower, {Karen M.} and Voon, {Hsiao P J} and Hughes, {Jim R} and David Garrick and Vip Viprakasit and Matthew Mitson and Gobbi, {Marco De} and Marco Marra and Andrew Morris and Aaron Abbott and Wilder, {Steven P.} and Stephen Taylor and Santos, {Guilherme M.} and Joe Cross and Helena Ayyub and Steven Jones and Jiannis Ragoussis and Daniela Rhodes and Ian Dunham and Higgs, {Douglas R.} and Gibbons, {Richard J}",
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Law, MJ, Lower, KM, Voon, HPJ, Hughes, JR, Garrick, D, Viprakasit, V, Mitson, M, Gobbi, MD, Marra, M, Morris, A, Abbott, A, Wilder, SP, Taylor, S, Santos, GM, Cross, J, Ayyub, H, Jones, S, Ragoussis, J, Rhodes, D, Dunham, I, Higgs, DR & Gibbons, RJ 2010, 'ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner', Cell, vol. 143, no. 3, pp. 367-378. https://doi.org/10.1016/j.cell.2010.09.023

ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. / Law, Martin J.; Lower, Karen M.; Voon, Hsiao P J; Hughes, Jim R; Garrick, David; Viprakasit, Vip; Mitson, Matthew; Gobbi, Marco De; Marra, Marco; Morris, Andrew; Abbott, Aaron; Wilder, Steven P.; Taylor, Stephen; Santos, Guilherme M.; Cross, Joe; Ayyub, Helena; Jones, Steven; Ragoussis, Jiannis; Rhodes, Daniela; Dunham, Ian; Higgs, Douglas R.; Gibbons, Richard J.

In: Cell, Vol. 143, No. 3, 29.10.2010, p. 367-378.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner

AU - Law, Martin J.

AU - Lower, Karen M.

AU - Voon, Hsiao P J

AU - Hughes, Jim R

AU - Garrick, David

AU - Viprakasit, Vip

AU - Mitson, Matthew

AU - Gobbi, Marco De

AU - Marra, Marco

AU - Morris, Andrew

AU - Abbott, Aaron

AU - Wilder, Steven P.

AU - Taylor, Stephen

AU - Santos, Guilherme M.

AU - Cross, Joe

AU - Ayyub, Helena

AU - Jones, Steven

AU - Ragoussis, Jiannis

AU - Rhodes, Daniela

AU - Dunham, Ian

AU - Higgs, Douglas R.

AU - Gibbons, Richard J

PY - 2010/10/29

Y1 - 2010/10/29

N2 - 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.

AB - 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.

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KW - HUMDISEASE

KW - PROTEINS

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M3 - Article

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