Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome

Yan Ouyang; Jennifer Salstrom; Silvia Diaz-Perez; Shareef Nahas; Youko Matsuno; David Dawson; Michael A. Teitell; Steve Horvath; Arthur D. Riggs; Richard A. Gatti; York Marahrens

doi:10.1016/j.bbrc.2005.09.122

Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome

Yan Ouyang, Jennifer Salstrom, Silvia Diaz-Perez, Shareef Nahas, Youko Matsuno, David Dawson, Michael A. Teitell, Steve Horvath, Arthur D. Riggs, Richard A. Gatti, York Marahrens

Genetics, Cell Biology and Development (CBS)

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.

Original language	English (US)
Pages (from-to)	875-880
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	337
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2005.09.122
State	Published - Nov 25 2005

Bibliographical note

Funding Information:
The authors thank Laura Gammill, Shaun Fouse, and Guoping Fan for critically reading the manuscript. ATR-kd and ATM-kd constructs were kindly provided by Robert Abraham (Burnham Institute, La Jolla, CA) and Michael Kastan (St. Jude Children’s Research Hospital, Memphis, TN), respectively. The human lymphoblastoid cell line expressing ATM-GFP was kindly provided by Susan Lees-Miller (University of Calgary, CA) and Kum Kum Khanna (Queensland Institute of Medical Research, AU). This work was supported by NIH R01 GM61007-01A1 (Y.M.), NIH R01 HD41451:01 (Y.M.), and by a grant from the Ataxia-Telangiectasia Medical Research Foundation.

Keywords

2-Aminopurine
ATM
ATR
Checkpoint
Heterochromatin
Inactive X chromosome

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10.1016/j.bbrc.2005.09.122

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title = "Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome",

abstract = "ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.",

keywords = "2-Aminopurine, ATM, ATR, Checkpoint, Heterochromatin, Inactive X chromosome",

author = "Yan Ouyang and Jennifer Salstrom and Silvia Diaz-Perez and Shareef Nahas and Youko Matsuno and David Dawson and Teitell, {Michael A.} and Steve Horvath and Riggs, {Arthur D.} and Gatti, {Richard A.} and York Marahrens",

note = "Funding Information: The authors thank Laura Gammill, Shaun Fouse, and Guoping Fan for critically reading the manuscript. ATR-kd and ATM-kd constructs were kindly provided by Robert Abraham (Burnham Institute, La Jolla, CA) and Michael Kastan (St. Jude Children{\textquoteright}s Research Hospital, Memphis, TN), respectively. The human lymphoblastoid cell line expressing ATM-GFP was kindly provided by Susan Lees-Miller (University of Calgary, CA) and Kum Kum Khanna (Queensland Institute of Medical Research, AU). This work was supported by NIH R01 GM61007-01A1 (Y.M.), NIH R01 HD41451:01 (Y.M.), and by a grant from the Ataxia-Telangiectasia Medical Research Foundation.",

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AU - Ouyang, Yan

AU - Salstrom, Jennifer

AU - Diaz-Perez, Silvia

AU - Nahas, Shareef

AU - Matsuno, Youko

AU - Dawson, David

AU - Teitell, Michael A.

AU - Horvath, Steve

AU - Riggs, Arthur D.

AU - Gatti, Richard A.

AU - Marahrens, York

N1 - Funding Information: The authors thank Laura Gammill, Shaun Fouse, and Guoping Fan for critically reading the manuscript. ATR-kd and ATM-kd constructs were kindly provided by Robert Abraham (Burnham Institute, La Jolla, CA) and Michael Kastan (St. Jude Children’s Research Hospital, Memphis, TN), respectively. The human lymphoblastoid cell line expressing ATM-GFP was kindly provided by Susan Lees-Miller (University of Calgary, CA) and Kum Kum Khanna (Queensland Institute of Medical Research, AU). This work was supported by NIH R01 GM61007-01A1 (Y.M.), NIH R01 HD41451:01 (Y.M.), and by a grant from the Ataxia-Telangiectasia Medical Research Foundation.

PY - 2005/11/25

Y1 - 2005/11/25

N2 - ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.

AB - ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.

KW - 2-Aminopurine

KW - ATM

KW - ATR

KW - Checkpoint

KW - Heterochromatin

KW - Inactive X chromosome

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Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome

Abstract

Bibliographical note

Keywords

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