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Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells

Xiaoming Sun, Aizhan Bizhanova, Timothy D. Matheson, Jun Yu, Lihua Julie Zhu, Paul D. Kaufman
doi: https://doi.org/10.1101/134767
Xiaoming Sun
1Department of Molecular, Cell and Cancer Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
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Aizhan Bizhanova
1Department of Molecular, Cell and Cancer Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
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Timothy D. Matheson
1Department of Molecular, Cell and Cancer Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
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Jun Yu
1Department of Molecular, Cell and Cancer Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
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Lihua Julie Zhu
1Department of Molecular, Cell and Cancer Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
2Program in Bioinformatics and Integrative Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
3Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA 01605, USA
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Paul D. Kaufman
1Department of Molecular, Cell and Cancer Biology University of Massachusetts Medical School, Worcester, MA 01605, USA
3Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA 01605, USA
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  • For correspondence: paul.kaufman1@umassmed.edu
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Abstract

Ki-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here, we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by co-depletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive × (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint-deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S phase progression and Xi heterochromatin maintenance in p21 checkpoint-proficient human cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 08, 2017.
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Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells
Xiaoming Sun, Aizhan Bizhanova, Timothy D. Matheson, Jun Yu, Lihua Julie Zhu, Paul D. Kaufman
bioRxiv 134767; doi: https://doi.org/10.1101/134767
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Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells
Xiaoming Sun, Aizhan Bizhanova, Timothy D. Matheson, Jun Yu, Lihua Julie Zhu, Paul D. Kaufman
bioRxiv 134767; doi: https://doi.org/10.1101/134767

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