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CFDP1 调控着着丝粒异染色质的稳定性，从而影响 RAN GTP 酶的活性和有丝分裂纺锤体的形成。

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

机构信息

School of Medicine and Dentistry, University of Rochester, Rochester, New York, United States of America.

出版信息

PLoS Biol. 2024 Apr 17;22(4):e3002574. doi: 10.1371/journal.pbio.3002574. eCollection 2024 Apr.

DOI:10.1371/journal.pbio.3002574
PMID:38630655
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11023358/
Abstract

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.

摘要

着丝粒异染色质在小卫星和大卫星上密集排列，由 H3K9me2/3 组蛋白、异染色质蛋白 HP1α 和组蛋白变体组成。在本研究中，我们试图确定由染色质因子 CFDP1 稳定的大卫星和小卫星上浓缩异染色质的机制，这些机制如何影响小 GTPase Ran 的活性，作为纺锤体形成的要求。CFDP1 与大卫星和小卫星上的异染色质共定位，是着丝粒异染色质结构稳定性所必需的。CENPA、HP1α 和 H2A.Z 异染色质成分的缺失导致纺锤体起始促进因子 RCC1 与小卫星和大卫星重复结合减少。由于 RCC1 结合减少导致 RanGTP 水平降低，干扰了有丝分裂纺锤体形成时染色质介导的微管起始。通过敲低组蛋白伴侣 ANP32E 在缺乏 CFDP1 的细胞和小鼠中恢复染色质 H2A.Z 水平，不仅部分恢复了依赖于 RCC1 的 RanGTP 水平，而且缓解了 CFDP1 敲除相关的颅面缺陷，并增加了 CFDP1/ANP32E 共沉默细胞中的微管起始。总之，这些研究为大卫星和小卫星上的浓缩异染色质与通过染色质蛋白 CFDP1 的微管起始之间提供了直接联系的证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/44f52d5a6bfc/pbio.3002574.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/8a6fee3961ef/pbio.3002574.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/b6df9312c010/pbio.3002574.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/4d2359b830fd/pbio.3002574.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/3042c8ce0a0f/pbio.3002574.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/2db8b4728a64/pbio.3002574.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/eba06b0abf84/pbio.3002574.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/351a78e133ee/pbio.3002574.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/8a729def870d/pbio.3002574.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/bc5712df655b/pbio.3002574.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/44f52d5a6bfc/pbio.3002574.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/8a6fee3961ef/pbio.3002574.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/b6df9312c010/pbio.3002574.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/4d2359b830fd/pbio.3002574.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/3042c8ce0a0f/pbio.3002574.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/2db8b4728a64/pbio.3002574.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/eba06b0abf84/pbio.3002574.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/351a78e133ee/pbio.3002574.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/8a729def870d/pbio.3002574.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/bc5712df655b/pbio.3002574.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9699/11023358/44f52d5a6bfc/pbio.3002574.g010.jpg

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