IKKα Shields 14-3-3σ, a G2/M Cell Cycle Checkpoint Gene, from Hypermethylation, Preventing Its Silencing

Feng Zhu; Xiaojun Xia; Bigang Liu; Jianjun Shen; Yuhui Hu; Maria Person; Yinling Hu

doi:10.1016/j.molcel.2007.05.042

IKKα Shields 14-3-3σ, a G₂/M Cell Cycle Checkpoint Gene, from Hypermethylation, Preventing Its Silencing

Feng Zhu, Xiaojun Xia, Bigang Liu, Jianjun Shen, Yuhui Hu, Maria Person, Yinling Hu

Academic Institute

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

57 Scopus citations

Abstract

We recently reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKα. However, the role of IKKα in maintaining genomic stability is unknown. Here we reported that IKKα-deficient keratinocytes had a defect in the G₂/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3σ, a cell cycle checkpoint protein. Trimethylated histone H3 lysine 9 (H3-K9) was found to associate with the histone trimethyltransferase Suv39h1 and DNA methyltransferase Dnmt3a in the methylated 14-3-3σ locus. Reintroduction of IKKα restored the expression of 14-3-3σ. IKKα was found to associate with H3 in 14-3-3σ, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3σ. IKKα mutants that failed to bind to H3 did not restore the expression of 14-3-3σ. Thus, IKKα protects the 14-3-3σ locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.

Original language	English (US)
Pages (from-to)	214-227
Number of pages	14
Journal	Molecular Cell
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2007.05.042
State	Published - Jul 20 2007

Keywords

CELLCYCLE
SIGNALING

ASJC Scopus subject areas

Molecular Biology

Access to Document

10.1016/j.molcel.2007.05.042

Cite this

@article{d58ee69265a4499cb941ac20cf473854,

title = "IKKα Shields 14-3-3σ, a G2/M Cell Cycle Checkpoint Gene, from Hypermethylation, Preventing Its Silencing",

abstract = "We recently reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKα. However, the role of IKKα in maintaining genomic stability is unknown. Here we reported that IKKα-deficient keratinocytes had a defect in the G2/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3σ, a cell cycle checkpoint protein. Trimethylated histone H3 lysine 9 (H3-K9) was found to associate with the histone trimethyltransferase Suv39h1 and DNA methyltransferase Dnmt3a in the methylated 14-3-3σ locus. Reintroduction of IKKα restored the expression of 14-3-3σ. IKKα was found to associate with H3 in 14-3-3σ, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3σ. IKKα mutants that failed to bind to H3 did not restore the expression of 14-3-3σ. Thus, IKKα protects the 14-3-3σ locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.",

keywords = "CELLCYCLE, SIGNALING",

author = "Feng Zhu and Xiaojun Xia and Bigang Liu and Jianjun Shen and Yuhui Hu and Maria Person and Yinling Hu",

note = "Funding Information: We thank K. Claypool for help with cell cycle analysis and K. Bouic for assistance with adenovirus preparation (University of California, San Diego); we would also like to thank M. Macleod for helpful discussions with the manuscript, V. Edwards for editorial assistance, and J. Parker-Thornburg for assistance with generating the Ikkα knock-in mice. This work was supported by grants from the National Cancer Institute (CA102510 and CA117314 to Y.H. and CA16672 to Comprehensive Center) and by a grant from the National Institute of Environmental Health Science (ES07784). The authors have no competing financial interests. ",

year = "2007",

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doi = "10.1016/j.molcel.2007.05.042",

language = "English (US)",

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journal = "Molecular Cell",

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T1 - IKKα Shields 14-3-3σ, a G2/M Cell Cycle Checkpoint Gene, from Hypermethylation, Preventing Its Silencing

AU - Zhu, Feng

AU - Xia, Xiaojun

AU - Liu, Bigang

AU - Shen, Jianjun

AU - Hu, Yuhui

AU - Person, Maria

AU - Hu, Yinling

N1 - Funding Information: We thank K. Claypool for help with cell cycle analysis and K. Bouic for assistance with adenovirus preparation (University of California, San Diego); we would also like to thank M. Macleod for helpful discussions with the manuscript, V. Edwards for editorial assistance, and J. Parker-Thornburg for assistance with generating the Ikkα knock-in mice. This work was supported by grants from the National Cancer Institute (CA102510 and CA117314 to Y.H. and CA16672 to Comprehensive Center) and by a grant from the National Institute of Environmental Health Science (ES07784). The authors have no competing financial interests.

PY - 2007/7/20

Y1 - 2007/7/20

N2 - We recently reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKα. However, the role of IKKα in maintaining genomic stability is unknown. Here we reported that IKKα-deficient keratinocytes had a defect in the G2/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3σ, a cell cycle checkpoint protein. Trimethylated histone H3 lysine 9 (H3-K9) was found to associate with the histone trimethyltransferase Suv39h1 and DNA methyltransferase Dnmt3a in the methylated 14-3-3σ locus. Reintroduction of IKKα restored the expression of 14-3-3σ. IKKα was found to associate with H3 in 14-3-3σ, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3σ. IKKα mutants that failed to bind to H3 did not restore the expression of 14-3-3σ. Thus, IKKα protects the 14-3-3σ locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.

AB - We recently reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKα. However, the role of IKKα in maintaining genomic stability is unknown. Here we reported that IKKα-deficient keratinocytes had a defect in the G2/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3σ, a cell cycle checkpoint protein. Trimethylated histone H3 lysine 9 (H3-K9) was found to associate with the histone trimethyltransferase Suv39h1 and DNA methyltransferase Dnmt3a in the methylated 14-3-3σ locus. Reintroduction of IKKα restored the expression of 14-3-3σ. IKKα was found to associate with H3 in 14-3-3σ, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3σ. IKKα mutants that failed to bind to H3 did not restore the expression of 14-3-3σ. Thus, IKKα protects the 14-3-3σ locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.

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KW - SIGNALING

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