IKKalpha shields 14-3-3sigma, a G(2)/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing.
We recently reported that a large proportion of aggressive squamous cell carcinomas of humans and mice express markedly reduced IKKalpha. However, the role of IKKalpha in maintaining genomic stability is unknown. Here we reported that IKKalpha-deficient keratinocytes had a defect in the G(2)/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3sigma, 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 14-3-3sigma locus. Reintroduction of IKKalpha restored the expression of 14-3-3sigma. IKKalpha was found to associate with H3 in 14-3-3sigma, which prevented access of Suv39h1 to H3, thereby preventing hypermethylation of 14-3-3sigma. IKKalpha mutants that failed to bind to H3 did not restore the expression of 14-3-3sigma. Thus, IKKalpha protects the 14-3-3sigma locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.
Zhu
Feng
F
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA.
Xia
Xiaojun
X
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA.
Liu
Bigang
B
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA.
Shen
Jianjun
J
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA.
Hu
Yuhui
Y
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA.
Person
Maria
M
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
Hu
Yinling
Y
Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX 78957, USA. Electronic address: yhu@mdanderson.org.
D048948:14-3-3 Proteins / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D016195:G2 Phase / Q000235:genetics; D020868:Gene Silencing; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D012097:Repressor Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism
D048948:14-3-3 Proteins; D017931:DNA Primers; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D006657:Histones; D012097:Repressor Proteins; C499130:Sfn protein, mouse; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase