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

The 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. © 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Citation

Vinutha Balachandra, Roshan L Shrestha, Colin M Hammond, Shinjen Lin, Ivo A Hendriks, Subhash Chandra Sethi, Lu Chen, Samantha Sevilla, Natasha J Caplen, Raj Chari, Tatiana S Karpova, Katherine McKinnon, Matthew Am Todd, Vishal Koparde, Ken Chih-Chien Cheng, Michael L Nielsen, Anja Groth, Munira A Basrai. DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains. The EMBO journal. 2024 Apr 10

PMID: 38600242

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