IKKα shields 14-3-3σ, a G2/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 IKK alpha. However, the role of IKK alpha in maintaining genomic stability is unknown. Here we reported that IKK alpha-deficient keratinocytes had a defect in the G(2)/M cell-cycle arrest in response to DNA damage due to downregulated 14-3-3 sigma, 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 14-3-3 sigma locus. Reintroduction of IKKa restored the expression of 14-3-3 sigma. IKKa was found to associate with H3 in 14-3-3 sigma which prevented access of Suv39h1 to H3: thereby preventing hypermethylation of 14-3-3 sigma. IKK alpha mutants that failed to bind to H3 did not restore the expression of 14-3-3 sigma. Thus, IKK alpha protects the 14-3-3 sigma locus from hypermethylation, which serves as a mechanism of maintaining genomic stability in keratinocytes.