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

Subhash Chandra Sethi·Roshan L Shrestha·Vinutha Balachandra·Tetsuya Hori·Luca Corda·Shinjen Lin·Laurent Ozbun·Tatiana S Karpova·Katherine McKinnon·Raj Chari·Gianluca Pegoraro·Ken Chih-Chien Cheng·Simona Giunta·Natasha J Caplen·Tatsuo Fukagawa·Munira A Basrai
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Abstract

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 EP400K1085G mutant, which lacks ATPase activity for histone exchange. Consistent with these results, EP400K1085G cells show increased CENP-A enrichment in chromatin and mislocalization to non-centromeric regions. Importantly, EP400K1085G 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.

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HumansCentromere Protein AChromosomal InstabilityChromatin Assembly and DisassemblyChromosomal Proteins, Non-HistoneHistonesAutoantigensHistone AcetyltransferasesChromatinTumor Suppressor Protein p53Cell LineATPase activityCENP-ACP: Molecular biologyEP400KAT5NuA4 HAT complexcentromerechromatin remodelerchromosomal instabilityhistone acetylationkinetochoreJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, N.I.H., Intramural

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Subhash Chandra Sethi, Roshan L Shrestha, Vinutha Balachandra, Tetsuya Hori, Luca Corda, Shinjen Lin, Laurent Ozbun, Tatiana S Karpova, Katherine McKinnon, Raj Chari, Gianluca Pegoraro, Ken Chih-Chien Cheng, Simona Giunta, Natasha J Caplen, Tatsuo Fukagawa, Munira A Basrai. 2025-10-24. Chromatin remodeling activity of EP400 safeguards chromosomal stability by preventing CENP-A mislocalization.. https://doi.org/10.1016/j.celrep.2025.116423

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