Cep57 organizes pericentriolar material through dual architectural modules and prevents human mosaic variegated aneuploidy
Abstract
Mosaic variegated aneuploidy (MVA) is a developmental disorder associated with chromosome segregation defects. Mutations in the centrosomal protein Cep57 cause MVA2 syndrome, yet the molecular basis of Cep57 function has remained unclear. Here, using MINFLUX nanoscopy, structural biology, biochemical approaches, and analyses of patient-derived cells, we show how Cep57 organizes the inner pericentriolar material (PCM) to support centriole biogenesis. We show that Cep57 acts as a molecular bridge between centriolar microtubules and the PCM through two architecturally distinct interactions. Its oligomeric C-terminus anchors to centriolar microtubules, whereas its dimeric N-terminus engages Cep63 through a conserved bundle-like interaction, thereby linking the Cep63–Cep152 platform to the centriole and recruiting Plk4 and other components required for procentriole formation. Analysis of primary T lymphocytes from MVA2 patients carrying the Cep63-binding-defective CEP57 ∆exon 3 mutation reveals a predominant centriole-duplication defect accompanied by minor centriole amplification, likely resulting from disorganized PCM-induced premature centriole disengagement. Our findings show Cep57 as a central architectural organizer that couples centriolar microtubules to the molecular machinery driving centriole biogenesis, providing a mechanistic framework for understanding centrosome dysfunction and aneuploidy-associated diseases.
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BibTeX
@article{ahn2026cep57,
title = {{Cep57 organizes pericentriolar material through dual architectural modules and prevents human mosaic variegated aneuploidy}},
author = {Jong Il Ahn and Jung-Eun Park and Hye-Yeoung Yun and Yan Zeng and Klara Kirsch and Vipin Kumar and Bonsu Ku and Arlene Bartolome and Harsha Ravishankar and Ruchi Bhardwaj and Rodolfo Ghirlando and Mahaiwon Shadang and Mohamadreza Fazel and David A. Ball and Jessica Matthias and Seung Jun Kim and Neerja Gupta and Jayanth Kumar Palanichamy and Tatiana S. Karpova and Kyung S. Lee},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77795-4},
url = {https://www.nature.com/articles/s41467-026-77795-4},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cep57 organizes pericentriolar material through dual architectural modules and prevents human mosaic variegated aneuploidy
AU - Jong Il Ahn
AU - Jung-Eun Park
AU - Hye-Yeoung Yun
AU - Yan Zeng
AU - Klara Kirsch
AU - Vipin Kumar
AU - Bonsu Ku
AU - Arlene Bartolome
AU - Harsha Ravishankar
AU - Ruchi Bhardwaj
AU - Rodolfo Ghirlando
AU - Mahaiwon Shadang
AU - Mohamadreza Fazel
AU - David A. Ball
AU - Jessica Matthias
AU - Seung Jun Kim
AU - Neerja Gupta
AU - Jayanth Kumar Palanichamy
AU - Tatiana S. Karpova
AU - Kyung S. Lee
PY - 2026
DA - 2026/09/30
JO - Nature Communications
DO - 10.1038/s41467-026-77795-4
UR - https://www.nature.com/articles/s41467-026-77795-4
AB - Mosaic variegated aneuploidy (MVA) is a developmental disorder associated with chromosome segregation defects. Mutations in the centrosomal protein Cep57 cause MVA2 syndrome, yet the molecular basis of Cep57 function has remained unclear. Here, using MINFLUX nanoscopy, structural biology, biochemical approaches, and analyses of patient-derived cells, we show how Cep57 organizes the inner pericentriolar material (PCM) to support centriole biogenesis. We show that Cep57 acts as a molecular bridge between centriolar microtubules and the PCM through two architecturally distinct interactions. Its oligomeric C-terminus anchors to centriolar microtubules, whereas its dimeric N-terminus engages Cep63 through a conserved bundle-like interaction, thereby linking the Cep63–Cep152 platform to the centriole and recruiting Plk4 and other components required for procentriole formation. Analysis of primary T lymphocytes from MVA2 patients carrying the Cep63-binding-defective CEP57 ∆exon 3 mutation reveals a predominant centriole-duplication defect accompanied by minor centriole amplification, likely resulting from disorganized PCM-induced premature centriole disengagement. Our findings show Cep57 as a central architectural organizer that couples centriolar microtubules to the molecular machinery driving centriole biogenesis, providing a mechanistic framework for understanding centrosome dysfunction and aneuploidy-associated diseases.
SN - 2041-1723
ER -