The histone H3/H4 chaperone CHAF1B prevents the mislocalization of CENP-A for chromosomal stability
| Autor: | Roshan L. Shrestha, Vinutha Balachandra, Jee Hun Kim, Austin Rossi, Pranathi Vadlamani, Subhash Chandra Sethi, Laurent Ozbun, Shinjen Lin, Ken Chin-Chien Cheng, Raj Chari, Tatiana S. Karpova, Gianluca Pegoraro, Daniel R. Foltz, Natasha J. Caplen, Munira A. Basrai |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Journal of Cell Science. 136 |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.260944 |
| Popis: | 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. Among the top five candidates in the screen – the depletion of which showed increased nuclear YFP–CENP-A fluorescence – were the histone chaperones CHAF1B (or p60) and CHAF1A (or p150). Follow-up validation and characterization experiments showed that CHAF1B-depleted cells exhibited CENP-A mislocalization, CIN phenotypes and increased enrichment of CENP-A in chromatin fractions. 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 identified regulators of CENP-A localization and defined a role for CHAF1B in preventing DAXX-dependent CENP-A mislocalization and CIN. |
| Databáze: | OpenAIRE |
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