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Histone H3/H4 chaperone CHAF1B prevents the mislocalization of CENP-A for chromosomal stability

  1. Author:
    Shrestha, Roshan L [ORCID]
    Balachandra, Vinutha
    Kim, Jee Hun
    Rossi, Austin
    Vadlamani, Pranathi [ORCID]
    Sethi, Subhash Chandra
    Ozbun, Laurent [ORCID]
    Lin, Shinjen
    Cheng, Ken Chin-Chien
    Chari,Raj
    Karpova, Tatiana S
    Pegoraro, Gianluca [ORCID]
    Foltz, Daniel R [ORCID]
    Caplen, Natasha J [ORCID]
    Basrai, Munira A [ORCID]

  2. Author Address

    Yeast Genome Stability Section, Genetics Branch, CCR, NCI, NIH, USA., Department of Biochemistry and Molecular Genetics, Northwestern University, USA., High-Throughput Imaging Facility (HiTIF), Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH, USA., Functional Genomics Facility, National Center for Advancing Translational Sciences, NIH, USA., Genome Modification Core, Laboratory Animal Sciences Program at the Frederick National Laboratory for Cancer Research, USA., Optical Microscopy Core, Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH, USA., Functional Genetics Section, Genetics Branch, CCR, NCI, NIH, USA.,
    1. Year: 2023
    2. Date: May 02
    3. Epub Date: 2023 05 02
  2. Journal: Journal of Cell Science
    1. 136
    2. 10
  4. Type of Article: Article
  5. Article Number: jcs260944
  1. Abstract:

    Restricting the localization of the evolutionarily conserved centromeric histone H3 variant CENP-A to centromeres prevents chromosomal instability (CIN). The mislocalization of CENP-A to non-centromeric regions contributes to CIN in yeasts, flies, and human cells. Even though overexpression and mislocalization of CENP-A have been reported in cancers the mechanisms responsible for its mislocalization remain poorly understood. Here, we used an imaging-based high-throughput RNAi screen to identify factors that prevent mislocalization of overexpressed YFP-tagged CENP-A (YFP-CENP-A) in HeLa cells. Amongst the top five lead candidates of the screen that showed increased nuclear YFP-CENP-A fluorescence were depletions of histone chaperones (CHAF1B/p60 and CHAF1A/p150). Follow-up validation and characterization experiments showed that CHAF1B-depleted cells exhibit CENP-A mislocalization, CIN phenotypes, and increased enrichment of CENP-A in the chromatin fraction. The depletion of DAXX, a histone H3.3 chaperone, suppressed CENP-A mislocalization and CIN in CHAF1B-depleted cells. We propose that in CHAF1B-depleted cells, DAXX promotes mislocalization of the overexpressed CENP-A to non-centromeric regions, resulting in CIN. In summary, we have identified regulators of CENP-A localization and defined a role for CHAF1B in preventing DAXX-dependent CENP-A mislocalization and CIN. © 2023. Published by The Company of Biologists Ltd.

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External Sources

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  2. DOI: 10.1242/jcs.260944
  3. PMID: 37129573
  4. PMCID: PMC10281518
  5. View record in Web of Science®
  6. WOS: 001030949100003
  7. PII : 307402

Library Notes

  1. Fiscal Year: FY2022-2023
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