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.
ASJC Scopus subject areas
- Molecular Biology