Induced detachment of acentric chromatin from mitotic chromosomes leads to their cytoplasmic localization at G(1) and the micronucleation by lamin reorganization at S phase

2000 ◽  
Vol 113 (4) ◽  
pp. 697-707 ◽  
Author(s):  
T. Tanaka ◽  
N. Shimizu
Keyword(s):  
Large Scale ◽  
Human Cancer ◽  
Strand Break ◽  
S Phase ◽  
Mitotic Chromosomes ◽  
Human Cancer Cells ◽  
Double Minutes ◽  
Nuclear Lamin ◽  
Hydroxyurea Treatment ◽  
Selective Incorporation

Acentric and atelomeric double minute chromatin found in human cancer cells are eliminated from cells by selective incorporation into the micronuclei. We showed previously that most of the micronuclei were formed at S phase and mediated by the nuclear bud-shaped structures that selectively entrap double minutes. In this paper, we have examined the behavior of double minutes in relation to the nuclear lamin protein in cell cycle-synchronized human COLO 320DM tumor cells. At the G(1) phase, we observed that a portion of double minutes was localized at the cytoplasm and showed no association with lamin. The frequency of this localization was increased by hydroxyurea, an inducer of micronuclei, if treated at the preceding S phase. The acentric double minutes were normally segregated to daughter cells by attaching to the mitotic chromosomes, and the hydroxyurea-treatment induced their detachment, possibly through the introduction of the double strand break. When the cells entered S phase, our data suggested that the lamin protein accumulated around the cytoplasmic double minutes at the proximity of the nucleus leading to the formation of the nuclear bud-shaped structure and the initiation of DNA replication. This association of cytoplasmic double minutes with lamin coincided with the large-scale rearrangement of the intranuclear lamin protein. The implication of these findings as well as their application to a broad spectrum of other acentric, atelomeric and autonomously replicating molecules are discussed.

scholarly journals Defining the mutation signatures of DNA polymerase θ in cancer genomes

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Taejoo Hwang ◽  
Shelley Reh ◽  
Yerkin Dunbayev ◽  
Yi Zhong ◽  
Yoko Takata ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Dna Polymerase ◽  
Human Cancer ◽  
Strand Break ◽  
Base Substitution ◽  
Cancer Therapies ◽  
End Joining ◽  
Dsb Repair ◽  
Human Cancer Cells ◽  
Insertion And Deletion

Abstract DNA polymerase theta (POLQ)-mediated end joining (TMEJ) is a distinct pathway for mediating DNA double-strand break (DSB) repair. TMEJ is required for the viability of BRCA-mutated cancer cells. It is crucial to identify tumors that rely on POLQ activity for DSB repair, because such tumors are defective in other DSB repair pathways and have predicted sensitivity to POLQ inhibition and to cancer therapies that produce DSBs. We define here the POLQ-associated mutation signatures in human cancers, characterized by short insertions and deletions in a specific range of microhomologies. By analyzing 82 COSMIC (Catalogue of Somatic Mutations in Cancer) signatures, we found that BRCA-mutated cancers with a higher level of POLQ expression have a greatly enhanced representation of the small insertion and deletion signature 6, as well as single base substitution signature 3. Using human cancer cells with disruptions of POLQ, we further show that TMEJ dominates end joining of two separated DSBs (distal EJ). Templated insertions with microhomology are enriched in POLQ-dependent distal EJ. The use of this signature analysis will aid in identifying tumors relying on POLQ activity.

Comparisons of the Frequencies and Molecular Spectra of HPRT Mutants When Human Cancer Cells Were X-Irradiated during G 1 or S Phase

1997 ◽  
Vol 148 (6) ◽  
pp. 548 ◽  
Author(s):  
Edith A. Leonhardt ◽  
Maxine Trinh ◽  
Helen B. Forrester ◽  
Robert T. Johnson ◽  
William C. Dewey
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
S Phase ◽  
Molecular Spectra ◽  
Human Cancer Cells

scholarly journals Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

2020 ◽  
Author(s):  
Yael Cohen-Sharir ◽  
James M. McFarland ◽  
Mai Abdusamad ◽  
Carolyn Marquis ◽  
Helen Tang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cellular Response ◽  
Large Scale ◽  
Spindle Assembly Checkpoint ◽  
Human Cancer ◽  
Spindle Assembly ◽  
Selective Vulnerability ◽  
Human Cancer Cell Lines ◽  
Human Cancer Cells ◽  
Diploid Cells

AbstractSelective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between near-diploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.

scholarly journals Dormant replication origin firing links replication stress to whole chromosomal instability in human cancer

2021 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Nicolas Boehly ◽  
Xiaoxiao Zhang ◽  
Benjamin O. Slusarenko ◽  
Magdalena Hennecke ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Chromosomal Instability ◽  
Replication Origin ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Replication Stress ◽  
S Phase ◽  
Origin Firing ◽  
Human Cancer Cells ◽  
Chromosome Missegregation

Chromosomal instability (CIN) is a hallmark of cancer and comprises structural CIN (S-CIN) and whole chromosome instability (W-CIN). Replication stress (RS), a condition of slowed or stalled DNA replication during S phase, has been linked to S-CIN, whereas defects in mitosis leading to chromosome missegregation and aneuploidy can account for W-CIN. It is well established that RS can activate additional replication origin firing that is considered as a rescue mechanism to suppress chromosomal instability in the presence of RS. In contrast, we show here that an increase in replication origin firing during S phase can contribute to W-CIN in human cancer cells. Increased origin firing can be specifically triggered by overexpression of origin firing genes including GINS1 and CDC45, whose elevated expression significantly correlates with W-CIN in human cancer specimens. Moreover, endogenous mild RS present in cancer cells characterized by W-CIN or modulation of the origin firing regulating ATR-CDK1-RIF1 axis induces dormant origin firing, which is sufficient to trigger chromosome missegregation and W-CIN. Importantly, chromosome missegregation upon increased dormant origin firing is mediated by increased microtubule growth rates leading to the generation of lagging chromosomes in mitosis, a condition prevalent in chromosomally unstable cancer cells. Thus, our study identified increased or dormant replication origin firing as a hitherto unrecognized, but cancer-relevant trigger for chromosomal instability.

scholarly journals System-Wide Analysis of Protein Acetylation and Ubiquitination Reveals a Diversified Regulation in Human Cancer Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 411 ◽  
Author(s):  
Hiroko Kozuka-Hata ◽  
Aya Kitamura ◽  
Tomoko Hiroki ◽  
Aiko Aizawa ◽  
Kouhei Tsumoto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Translational Control ◽  
Large Scale ◽  
Human Cancer ◽  
Initiation Factor ◽  
Protein Acetylation ◽  
Human Cancer Cell Lines ◽  
Human Cancer Cells ◽  
Lysine Modification

Post-translational modifications are known to be widely involved in the regulation of various biological processes, through the extensive diversification of each protein function at the cellular network level. In order to unveil the system-wide function of the protein lysine modification in cancer cell signaling, we performed global acetylation and ubiquitination proteome analyses of human cancer cells, based on high-resolution nanoflow liquid chromatography–tandem mass spectrometry, in combination with the efficient biochemical enrichment of target modified peptides. Our large-scale proteomic analysis enabled us to identify more than 5000 kinds of ubiquitinated sites and 1600 kinds of acetylated sites, from representative human cancer cell lines, leading to the identification of approximately 900 novel lysine modification sites in total. Very interestingly, 236 lysine residues derived from 141 proteins were found to be modified with both ubiquitination and acetylation. As a consequence of the subsequent motif extraction analyses, glutamic acid (E) was found to be highly enriched at the position (−1) for the lysine acetylation sites, whereas the same amino acid was relatively dispersed along the neighboring residues of the lysine ubiquitination sites. Our pathway analysis also indicated that the protein translational control pathways, such as the eukaryotic initiation factor 2 (EIF2) and the ubiquitin signaling pathways, were highly enriched in both of the acetylation and ubiquitination proteome data at the network level. This report provides the first integrative description of the protein acetylation and ubiquitination-oriented systematic regulation in human cancer cells.

scholarly journals Inhibition of Rac1 activity induces G1/S phase arrest through the GSK3/cyclin D1 pathway in human cancer cells

2014 ◽  
Vol 32 (4) ◽  
pp. 1395-1400 ◽  
Author(s):  
LINNA LIU ◽  
HONGMEI ZHANG ◽  
LEI SHI ◽  
WENJUAN ZHANG ◽  
JUANLI YUAN ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Cancer Cells ◽  
Human Cancer ◽  
S Phase ◽  
Human Cancer Cells ◽  
Phase Arrest ◽  
Rac1 Activity ◽  
S Phase Arrest

scholarly journals Replication Stress, Defective S-phase Checkpoint and Increased Death in Plk2-Deficient Human Cancer Cells

Cell Cycle ◽  
2007 ◽  
Vol 6 (20) ◽  
pp. 2571-2578 ◽  
Author(s):  
Elizabeth M. Matthew ◽  
Timothy J. Yen ◽  
David T. Dicker ◽  
Jay F. Dorsey ◽  
Wensheng Yang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Replication Stress ◽  
S Phase ◽  
Human Cancer Cells ◽  
S Phase Checkpoint
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