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Ki-67 is necessary during DNA replication for forks protection and genome stability

ABSTRACT: Ki-67 molecular functions and properties have remained quite obscure for a long time, despite its importance as a major proliferation marker in clinic. Only recently it has been shown that Ki-67 has a major role in the formation of the mitotic chromosome periphery compartment, and it is a protein phosphatase 1 (PP1) binding protein. Understanding Ki-67 functions at different stages of the cell cycle has been so far hindered by the fact that the different phenotypes observed in cells upon Ki-67 depletion could be the outcome of secondary effects. Here, by using Auxin-inducible-degron (AID) system, we show that Ki-67 degradation at the G1/S boundary causes the disassembly of the replication machinery and leads to DNA damage. This triggers the interferon response and causes replication delay. Our results support the model whereby Ki-67 contributes to replication forks protection, and it is important for timely DNA replication and genome maintenance.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Paola Vagnarelli

LAB HEAD: Paola Vagnarelli

PROVIDER: PXD037513 | Pride | 2024-04-13

REPOSITORIES: Pride

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			Action	DRS
	Stamatiou_etal_2022_HCT116-APEX_vs_HCT116-unmodified.7z	Other
	Stamatiou_etal_2022_HCT116-APEX_vs_HCT116-unmodified.raw	Raw
	Stamatiou_etal_2022_HCT116_Ki67-Aid_auxin_vs._control_PE.7z	Other
	Stamatiou_etal_2022_HCT116_Ki67-Aid_auxin_vs._control_PE_F1.raw	Raw
	Stamatiou_etal_2022_HCT116_Ki67-Aid_auxin_vs._control_PE_F2.raw	Raw

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RNA sequencing from publication: Ki-67 is necessary during DNA replication for forks protection and genome stability

Project description:Ki-67 is highly expressed in proliferating cells, characteristic that made the protein a very important marker widely used in the clinic. However, its molecular functions and properties have remained quite obscure for a long time. Only recently important discoveries have shed some light on Ki-67 function and shown that Ki-67 has a major role in the formation of mitotic chromosome periphery compartment, it is associated with protein phosphatase one (PP1) and regulates chromatin structure in both interphase and mitosis. However, it is still difficult to understand the specific molecular function of this protein since the different phenotypes could be the outcome of secondary effects. In fact, the studies so far conducted have used either RNAi or knock-out cells: the former could lead to phenotypes which are the sum of a cascade of complex events while the latter could be the outcome of compensatory mechanisms taking place. To address these problems, we have generated a cell line system for the rapid manipulation of Ki-67 by introducing an Auxin-inducible-degron (AID) tag in both alleles of the endogenous Ki-67 gene in HCT116 cells. This AID system allows rapid protein depletion by the addition of Auxin.

2024-04-07 | E-MTAB-12279 | biostudies-arrayexpress

Ki-67 organises heterochromatin during cell proliferation

Project description:Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not inhibit cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 at heterochromatin was strongly reduced. Overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression.

2018-10-26 | PXD003551 | Pride

Human HeLa cells: Control shRNA vs Ki-67 shRNA, in vitro and xenografts

Project description:Transcriptional profiling of isogenic human cervical cancer cell line HCT-116, comparing cells treated with control shRNA or with Ki-67 shRNA, grown either in vitro or as tumours in nude mice. The aim was to assess effects of loss of Ki-67 on gene expression during exponential cell growth and in tumours

2021-02-18 | GSE162365 | GEO

In-depth Proteomics of Malignant Luminal Breast Cancer

Project description:In-depth clinical proteomic analysis of laser-microdissected HOT lesions of five luminal B breast cancer Ki-67 high subtype.

2020-10-12 | PXD021912 | JPOST Repository

Next Generation Sequencing Quantitative Analysis of Wild Type and Mki67-/- 4T1 mouse mammary carcinoma cell histone modification

Project description:Ki-67 chromatin associated proteins that has been shown to broadly affect the transcription profiles of cells when knocked-out. To understand if those transcriptome changes are regulated by histone modifications we performed ChIP-seq analysis for three of the most recognized histone marks (H3K27me3, H3K4me3 and H3K27ac) as the regulators of gene expression, in wild-type (WT) and Ki-67 knockout (Mki67−/−) mouse 4T1 cells.

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Raw RNA-seq data from control and Ki-67-depleted HCT116 human colon cancer cells

Project description:Raw RNA-seq data from control and Ki-67-depleted HCT116 human colon cancer cells

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Project description:Primary objectives: The primary endpoint of the study is to estimate the activity of allopurinol compared with placebo on the change in cell proliferation by assessment of Ki-67 Primary endpoints: The primary endpoint of the study is to estimate the activity of allopurinol compared with placebo on the change in cell proliferation by assessment of Ki-67, a biomarker of cell proliferation, in CRC tissue at baseline tumor or polyp biopsy and after 4 weeks of allopurinol treatment surgical resection specimen .

| 2519335 | ecrin-mdr-crc

RNA sequencing from publication: Ki-67 is necessary during DNA replication for forks protection and genome stability

Project description:RNA sequencing from publication: Ki-67 is necessary during DNA replication for forks protection and genome stability

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Ki-67 promotes carcinogenesis by enabling global transcriptional programmes

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SUMO Proteomics Analyses Identify Protein Inhibitor of Activated STAT-Mediated Regulatory Networks Involved in Cell Cycle and Cell Proliferation

Project description:Protein inhibitor of activated STAT (PIAS) are E3 SUMO ligases playing important roles in protein stability and signaling transduction pathways. PIAS proteins are overexpressed in the triple-negative breast cancer cell line MDA-MB-231, and PIAS knockout (KO) results in a reduction in cell proliferation and cell arrest in S phase. However, the molecular mechanisms underlying PIAS functions in cell proliferation and cell cycle remain largely unknown. Here, we used quantitative SUMO proteomics to explore the regulatory role of PIAS SUMO E3 ligases upon CRISPR/Cas9 KO of individual PIAS. A total of 1422 sites were identified, and around 10% of SUMO sites were regulated following KO of one or more PIAS genes. We identified protein substrates that were either specific to individual PIAS ligase or regulated by several PIAS ligases. Ki-67 and TOP2A, which are involved in cell proliferation and epithelial-to-mesenchymal transition, are SUMOylated at several lysine residues by all PIAS ligases, suggesting a level of redundancy between these proteins. Confocal microscopy and biochemical experiments revealed that SUMOylation regulated TOP2A protein stability, while this modification is involved in the recruitment of Ki-67 nucleolar proteins containing SUMO interacting motif. These results provide novel insights into both the redundant and specific regulatory mechanisms of cell proliferation and cell cycle mediated by PIAS SUMO E3 ligases.

2023-02-02 | PXD023841 | Pride

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