Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells

Su, Jie; Zhu, Dandan; Huo, Zijun; Gingold, Julian A.; Ang, Yen‐Sin; Tu, Jian; Zhou, Ruoji; Lin, Yu Fen; Luo, Haidan; Yang, Huiling; Zhao, Ruiying; Schaniel, Christoph; Moore, Kateri; Lemischka, Ihor R.; Lee, Dung‐Fang

doi:10.1016/j.celrep.2019.07.011

Cited by 12 publications

(12 citation statements)

References 41 publications

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“…Our research is consistent with -and suggests a mechanism for-previous evidence showing that Wnt secretion controls genome stability in mouse embryonic stem cells (Augustin et al, 2017). Interestingly, it has been shown recently that self-renewal of pluripotent cells is tightly linked to their genome integrity (Su et al, 2019). Hence, mitotic Wnt signaling may contribute to the known TCF/b-catenin functions in stem cell renewal by preventing chromosome instability.…”

Section: Discussionsupporting

confidence: 91%

Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis

Bufe

Arco

Hennecke

et al. 2020

Preprint

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Canonical Wnt signaling plays critical roles in development and tissue renewal by regulating β-catenin target genes. Recent evidence showed that β-catenin-independent Wnt signaling is also required for faithful execution of mitosis. This mitotic Wnt signaling functions through Wnt-dependent stabilization of proteins (Wnt/STOP), as well as through components of the LRP6 signalosome. However, the targets and specific functions of mitotic Wnt signaling still remain uncharacterized. Using phosphoproteomics, we identified that Wnt signaling regulates the microtubule depolymerase KIF2A during mitosis. We found that Dishevelled recruits KIF2A via its N-terminal and motor domains, which is further promoted upon LRP6 signalosome formation during mitosis. We show that Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A localization at the spindle. Accordingly, Wnt signaling promotes chromosome congression and alignment by monitoring KIF2A protein levels at the spindle poles both in somatic cells and in pluripotent stem cells. Our findings highlight a novel function of Wnt signaling during cell division, which could have important implications for genome maintenance, notably in stem cells.SIGNIFICANCEWnt signaling plays essential roles in embryonic patterning, stem cell renewal, and cell cycle progression from G1 to S phase via the regulation of β-catenin target genes. Here, we show that Wnt signaling also promotes faithful execution of mitosis by ensuring chromosome congression and alignment before cell division, including in pluripotent stem cells. We demonstrate that the Wnt signaling transducer Dishevelled recruits the mitotic kinesin KIF2A, and mediates its binding to the spindle. KIF2A is a microtubule depolymerase that controls chromosome alignment and congression during mitosis. Consequently, we found that inhibition of Wnt signaling leads to KIF2A-dependent chromosome congression and alignment defects.

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Section: Discussionsupporting

confidence: 91%

Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis

Bufe

Arco

Hennecke

et al. 2020

Preprint

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“…The knockdown of BUB1 in the MDA-MB-231 breast cancer cell line reduced the CSC potential [39]. The depletion of BUB1B in embryonic stem cells (ESCs) compromised self-renewal and led to consequent differentiation by the mechanism of DNA damage/genome instability, activating p53, and culminating in ESC differentiation [40]. CDC20 was usually enriched in CD44+ prostate CSCs [41].…”

Section: Discussionmentioning

confidence: 99%

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Zhang

Tseng

Lien

et al. 2020

Genes

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Cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, lead to therapeutic resistance in lung cancer. In this study, we aimed to investigate the expressions of stem cell-related genes in lung adenocarcinoma (LUAD). The stemness index based on mRNA expression (mRNAsi) was utilized to analyze LUAD cases in the Cancer Genome Atlas (TCGA). First, mRNAsi was analyzed with differential expressions, survival analysis, clinical stages, and gender in LUADs. Then, the weighted gene co-expression network analysis was performed to discover modules of stemness and key genes. The interplay among the key genes was explored at the transcription and protein levels. The enrichment analysis was performed to annotate the function and pathways of the key genes. The expression levels of key genes were validated in a pan-cancer scale. The pathological stage associated gene expression level and survival probability were also validated. The Gene Expression Omnibus (GEO) database was additionally used for validation. The mRNAsi was significantly upregulated in cancer cases. In general, the mRNAsi score increases according to clinical stages and differs in gender significantly. Lower mRNAsi groups had a better overall survival in major LUADs, within five years. The distinguished modules and key genes were selected according to the correlations to the mRNAsi. Thirteen key genes (CCNB1, BUB1, BUB1B, CDC20, PLK1, TTK, CDC45, ESPL1, CCNA2, MCM6, ORC1, MCM2, and CHEK1) were enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Eight of the thirteen genes have been reported to be associated with the CSC characteristics. However, all of them have been previously ignored in LUADs. Their expression increased according to the pathological stages of LUAD, and these genes were clearly upregulated in pan-cancers. In the GEO database, only the tumor necrosis factor receptor associated factor-interacting protein (TRAIP) from the blue module was matched with the stemness microarray data. These key genes were found to have strong correlations as a whole, and could be used as therapeutic targets in the treatment of LUAD, by inhibiting the stemness features.

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“…For patients with SCLC, the higher the expression level of BUB1B is, the worse the prognosis (Liao et al, 2019). BUB1B has also been found to regulate the development of stem cells; for example, in experiments with embryonic stem cells, Su et al (2019) found that knocking down BUB1B can lead to DNA damage and other forms of genomic instability, activate p53 and eventually lead to embryonic stem cell differentiation and possibly cancer.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Reveals Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma

2020

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Background: Tumor stem cells play important roles in the survival, proliferation, metastasis and recurrence of tumors. We aimed to identify new prognostic biomarkers for lung squamous cell carcinoma (LUSC) based on the cancer stem cell theory. Methods: RNA-seq data and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Weighted gene coexpression network analysis (WGCNA) was applied to identify significant modules and hub genes, and prognostic signatures were constructed with the prognostic hub genes. Results: LUSC patients in the TCGA database have higher mRNA expression-based stemness index (mRNAsi) in tumor tissue than in adjacent normal tissue. In addition, some clinical features and outcomes were highly correlated with the mRNAsi. WGCNA revealed that the pink and yellow modules were the most significant modules related to the mRNAsi; the top 10 hub genes in the pink module were enriched mostly in epidermal development, the secretory granule membrane, receptor regulator activity and the cytokine-cytokine receptor interaction. The protein-protein interaction (PPI) network revealed that the top 10 hub genes were significantly correlated with each other at the transcriptional level. In addition, the top 10 hub genes were all highly expressed in LUSC, and some were differentially expressed in different TNM stages. Regarding the survival analysis, the nomogram of a prognostic signature with three hub genes showed high predictive value. Conclusion: mRNAsi-related hub genes could be a potential biomarker of LUSC.

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Genomic Integrity Safeguards Self-Renewal in Embryonic Stem Cells

Cited by 12 publications

References 41 publications

Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis

Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Bioinformatics Analysis Reveals Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma

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