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

  1. Author:
    Balachandra, Vinutha
    Shrestha, Roshan L
    Hammond, Colin M [ORCID]
    Lin, Shinjen
    Hendriks, Ivo A [ORCID]
    Sethi, Subhash Chandra
    Chen, Lu
    Sevilla, Samantha [ORCID]
    Caplen, Natasha J
    Chari,Raj [ORCID]
    Karpova, Tatiana S [ORCID]
    McKinnon, Katherine
    Todd, Matthew Am [ORCID]
    Koparde,Vishal [ORCID]
    Cheng, Ken Chih-Chien
    Nielsen, Michael L
    Groth, Anja
    Basrai, Munira A [ORCID]

  2. Author Address

    Yeast Genome Stability Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. colin.hammond@liverpool.ac.uk., Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. colin.hammond@liverpool.ac.uk., Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. colin.hammond@liverpool.ac.uk., Functional Genomics Laboratory, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA., Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Genome Modification Core (GMC), Frederick National Lab for Cancer Research, Frederick, MD, USA., Optical Microscopy Core, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Flow Cytometry Core, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Yeast Genome Stability Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. basraim@nih.gov.,
    1. Year: 2024
    2. Date: Apr 10
    3. Epub Date: 2024 04 10
  2. Journal: The EMBO Journal
  4. Type of Article: Article
  1. Abstract:

    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.

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  2. DOI: 10.1038/s44318-024-00093-6
  3. PMID: 38600242
  4. PII : 10.1038/s44318-024-00093-6

Library Notes

  1. Fiscal Year: FY2023-2024
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