Chromatin remodeling activity of EP400 safeguards chromosomal stability by preventing CENP-A mislocalization

The mislocalization of CENP-A to non-centromeric regions contributes to chromosomal instability (CIN). The NuA4 histone acetyltransferase complex members EP400 and KAT5 regulate histone H2A.Z-H2B exchange and acetylation of histones, respectively. Overexpression of CENP-A and mutations in NuA4 components are observed in cancers. Here, we define a role for the chromatin remodeling activity of EP400, a top hit in RNAi screens for increased nuclear levels of CENP-A, in preventing CENP-A mislocalization and CIN. Mechanistically, we demonstrate a defect in the extraction of CENP-A from chromatin in cells expressing the EP400^K1085G mutant, which lacks ATPase activity for histone exchange. Consistent with these results, EP400^K1085G cells show increased CENP-A enrichment in chromatin and mislocalization to non-centromeric regions. Importantly, EP400^K1085G cells exhibit CIN phenotypes in stable, near-diploid RPE1 cells with wild-type p53. In summary, our findings expand the role of EP400 from nucleosome destabilization for histone exchange to preventing the stable association of CENP-A with non-centromeric regions and CIN.