CFDP1 regulates the stability of pericentric heterochromatin thereby affecting RAN GTPase activity and mitotic spindle formation.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2003]-

Chromatin*/metabolism ; Heterochromatin*/metabolism ; Nuclear Proteins*/genetics ; Nuclear Proteins*/metabolism; Animals ; Mice ; Histones/metabolism ; ran GTP-Binding Protein/metabolism ; Spindle Apparatus/metabolism

The densely packed centromeric heterochromatin at minor and major satellites is comprised of H3K9me2/3 histones, the heterochromatin protein HP1α, and histone variants. In the present study, we sought to determine the mechanisms by which condensed heterochromatin at major and minor satellites stabilized by the chromatin factor CFDP1 affects the activity of the small GTPase Ran as a requirement for spindle formation. CFDP1 colocalized with heterochromatin at major and minor satellites and was essential for the structural stability of centromeric heterochromatin. Loss of CENPA, HP1α, and H2A.Z heterochromatin components resulted in decreased binding of the spindle nucleation facilitator RCC1 to minor and major satellite repeats. Decreased RanGTP levels as a result of diminished RCC1 binding interfered with chromatin-mediated microtubule nucleation at the onset of mitotic spindle formation. Rescuing chromatin H2A.Z levels in cells and mice lacking CFDP1 through knock-down of the histone chaperone ANP32E not only partially restored RCC1-dependent RanGTP levels but also alleviated CFDP1-knockout-related craniofacial defects and increased microtubule nucleation in CFDP1/ANP32E co-silenced cells. Together, these studies provide evidence for a direct link between condensed heterochromatin at major and minor satellites and microtubule nucleation through the chromatin protein CFDP1.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Gopinathan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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R01 DE013095 United States DE NIDCR NIH HHS; R01 DE019463 United States DE NIDCR NIH HHS; R01 DE026198 United States DE NIDCR NIH HHS; R01 DE027686 United States DE NIDCR NIH HHS

0 (Cfdp1 protein, mouse)

Date Created: 20240417 Date Completed: 20240419 Latest Revision: 20240521

20240522

PMC11023358

10.1371/journal.pbio.3002574

38630655