DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains
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DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains. / Balachandra, Vinutha; Shrestha, Roshan L; Hammond, Colin M; Lin, Shinjen; Hendriks, Ivo A; Sethi, Subhash Chandra; Chen, Lu; Sevilla, Samantha; Caplen, Natasha J; Chari, Raj; Karpova, Tatiana S; McKinnon, Katherine; Todd, Matthew Am; Koparde, Vishal; Cheng, Ken Chih-Chien; Nielsen, Michael L; Groth, Anja; Basrai, Munira A.
I: The EMBO Journal, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains
AU - Balachandra, Vinutha
AU - Shrestha, Roshan L
AU - Hammond, Colin M
AU - Lin, Shinjen
AU - Hendriks, Ivo A
AU - Sethi, Subhash Chandra
AU - Chen, Lu
AU - Sevilla, Samantha
AU - Caplen, Natasha J
AU - Chari, Raj
AU - Karpova, Tatiana S
AU - McKinnon, Katherine
AU - Todd, Matthew Am
AU - Koparde, Vishal
AU - Cheng, Ken Chih-Chien
AU - Nielsen, Michael L
AU - Groth, Anja
AU - Basrai, Munira A
N1 - © 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s44318-024-00093-6
DO - 10.1038/s44318-024-00093-6
M3 - Journal article
C2 - 38600242
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
ER -
ID: 389361358