DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains

Author:

Balachandra Vinutha,Shrestha Roshan L,Hammond Colin MORCID,Lin Shinjen,Hendriks Ivo AORCID,Sethi Subhash Chandra,Chen Lu,Sevilla SamanthaORCID,Caplen Natasha J,Chari RajORCID,Karpova Tatiana SORCID,McKinnon Katherine,Todd Matthew AMORCID,Koparde VishalORCID,Cheng Ken Chih-Chien,Nielsen Michael L,Groth Anja,Basrai Munira AORCID

Abstract

AbstractThe centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3–H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3–H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3–H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.

Funder

HHS | NIH | NCI | Center for Cancer Research

HHS | NIH | National Cancer Institute

Independent Research Fund Denmark, European Union’s Horizon 2020 research and innovation program, Danish Cancer Society

European Research Council, Lund-beck Foundation, Independent Research Fund Denmark, Novo Nordisk Foundation

NIH Intramural Research Program, Intramural Research Program of the National Center for Advancing Translational Sciences

Publisher

Springer Science and Business Media LLC

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