scholarly journals The wages of CIN

2008 ◽  
Vol 180 (4) ◽  
pp. 661-663 ◽  
Author(s):  
Karen W. Yuen ◽  
Arshad Desai
Keyword(s):  
Cancer Cells ◽  
Solid Tumors ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Spindle Checkpoint ◽  
Human Cells ◽  
Normal Cells ◽  
Chromosome Missegregation ◽  
Cell Biol ◽  
The Relationship

Aneuploidy and chromosome instability (CIN) are hallmarks of the majority of solid tumors, but the relationship between them is not well understood. In this issue, Thompson and Compton (Thompson, S.L., and D.A. Compton. 2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell. Biol. 180:665–672) investigate the mechanism of CIN in cancer cells and find that CIN arises primarily from defective kinetochore–spindle attachments that evade detection by the spindle checkpoint and persist into anaphase. They also explore the consequences of artificially elevating chromosome missegregation in otherwise karyotypically normal cells. Their finding that induced aneuploidy is rapidly selected against suggests that the persistence of aneuploid cells in tumors requires not only chromosome missegregation but also additional, as yet poorly defined events.

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 Examining the link between chromosomal instability and aneuploidy in human cells

2008 ◽  
Vol 180 (4) ◽  
pp. 665-672 ◽  
Author(s):  
Sarah L. Thompson ◽  
Duane A. Compton
Keyword(s):  
Chromosome Segregation ◽  
Chromosomal Instability ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Human Cells ◽  
Phenotypic Changes ◽  
Chromosome Missegregation ◽  
Chromosome Attachment ◽  
Diploid Cells ◽  
The Relationship

Solid tumors can be highly aneuploid and many display high rates of chromosome missegregation in a phenomenon called chromosomal instability (CIN). In principle, aneuploidy is the consequence of CIN, but the relationship between CIN and aneuploidy has not been clearly defined. In this study, we use live cell imaging and clonal cell analyses to evaluate the fidelity of chromosome segregation in chromosomally stable and unstable human cells. We show that improper microtubule–chromosome attachment (merotely) is a cause of chromosome missegregation in unstable cells and that increasing chromosome missegregation rates by elevating merotely during consecutive mitoses generates CIN in otherwise stable, near-diploid cells. However, chromosome missegregation compromises the proliferation of diploid cells, indicating that phenotypic changes that permit the propagation of nondiploid cells must combine with elevated chromosome missegregation rates to generate aneuploid cells with CIN.

scholarly journals Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability

2016 ◽  
Vol 27 (19) ◽  
pp. 2911-2923 ◽  
Author(s):  
Shengyao Chen ◽  
Jane R. Stout ◽  
Sathiya Dharmaiah ◽  
Sarah Yde ◽  
Brian R. Calvi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Genomic Instability ◽  
Chromosomal Instability ◽  
Tumor Heterogeneity ◽  
Therapy Resistance ◽  
Human Cells ◽  
Diverse Population ◽  
Daughter Cells ◽  
Chromosome Missegregation ◽  
Experimentally Induced

Polyploid cancer cells exhibit chromosomal instability (CIN), which is associated with tumorigenesis and therapy resistance. The mechanisms that induce polyploidy and how these mechanisms contribute to CIN are not fully understood. Here we evaluate CIN in human cells that become polyploid through an experimentally induced endoreplication cycle. When these induced endoreplicating cells (iECs) returned to mitosis, it resulted in aneuploidy in daughter cells. This aneuploidy resulted from multipolar divisions, chromosome missegregation, and failure in cytokinesis. The iECs went through several rounds of division, ultimately spawning proliferative cells of reduced ploidy. iECs have reduced levels of the kinesin-14 HSET, which likely accounts for the multipolar divisions, and overexpression of HSET reduced spindle multipolarity. However, HSET overexpression had only mild effects on CIN, suggesting that additional defects must contribute to genomic instability in dividing iECs. Overall our results suggest that transient endoreplication cycles generate a diverse population of proliferative aneuploid cells that have the potential to contribute to tumor heterogeneity.

scholarly journals The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels

2020 ◽  
Vol 52 (4) ◽  
pp. 643-657 ◽  
Author(s):  
Abdul Basit ◽  
Min-Guk Cho ◽  
Eui-Yun Kim ◽  
Dohyeong Kwon ◽  
Suk-Jo Kang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Adverse Effects ◽  
Cancer Cells ◽  
Chromosomal Instability ◽  
Interferon Regulatory Factor ◽  
Mitotic Arrest ◽  
Regulatory Factor ◽  
Chromosome Missegregation ◽  
Sting Pathway ◽  
Innate Immunity Pathway

Abstract Chromosomal instability (CIN) in cancer cells has been reported to activate the cGAS–STING innate immunity pathway via micronuclei formation, thus affecting tumor immunity and tumor progression. However, adverse effects of the cGAS/STING pathway as they relate to CIN have not yet been investigated. We addressed this issue using knockdown and add-back approaches to analyze each component of the cGAS/STING/TBK1/IRF3 pathway, and we monitored the extent of CIN by measuring micronuclei formation after release from nocodazole-induced mitotic arrest. Interestingly, knockdown of cGAS (cyclic GMP-AMP synthase) along with induction of mitotic arrest in HeLa and U2OS cancer cells clearly resulted in increased micronuclei formation and chromosome missegregation. Knockdown of STING (stimulator of interferon genes), TBK1 (TANK-binding kinase-1), or IRF3 (interferon regulatory factor-3) also resulted in increased micronuclei formation. Moreover, transfection with cGAMP, the product of cGAS enzymatic activity, as well as add-back of cGAS WT (but not catalytic-dead mutant cGAS), or WT or constitutively active STING (but not an inactive STING mutant) rescued the micronuclei phenotype, demonstrating that all components of the cGAS/STING/TBK1/IRF3 pathway play a role in preventing CIN. Moreover, p21 levels were decreased in cGAS-, STING-, TBK1-, and IRF3-knockdown cells, which was accompanied by the precocious G2/M transition of cells and the enhanced micronuclei phenotype. Overexpression of p21 or inhibition of CDK1 in cGAS-depleted cells reduced micronuclei formation and abrogated the precocious G2/M transition, indicating that the decrease in p21 and the subsequent precocious G2/M transition is the main mechanism underlying the induction of CIN through disruption of cGAS/STING signaling.

scholarly journals Chromosome oscillation promotes Aurora A–dependent Hec1 phosphorylation and mitotic fidelity

2021 ◽  
Vol 220 (7) ◽  
Author(s):  
Kenji Iemura ◽  
Toyoaki Natsume ◽  
Kayoko Maehara ◽  
Masato T. Kanemaki ◽  
Kozo Tanaka
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Chromosomal Instability ◽  
Oscillation Amplitude ◽  
Cancer Cell Lines ◽  
Aurora A ◽  
Chromosome Missegregation ◽  
Phosphorylation Level ◽  
Chromosome Motion

Most cancer cells show chromosomal instability, a condition where chromosome missegregation occurs frequently. We found that chromosome oscillation, an iterative chromosome motion during metaphase, is attenuated in cancer cell lines. We also found that metaphase phosphorylation of Hec1 at serine 55, which is mainly dependent on Aurora A on the spindle, is reduced in cancer cell lines. The Aurora A–dependent Hec1-S55 phosphorylation level was regulated by the chromosome oscillation amplitude and vice versa: Hec1-S55 and -S69 phosphorylation by Aurora A is required for efficient chromosome oscillation. Furthermore, enhancement of chromosome oscillation reduced the number of erroneous kinetochore–microtubule attachments and chromosome missegregation, whereas inhibition of Aurora A during metaphase increased such errors. We propose that Aurora A–mediated metaphase Hec1-S55 phosphorylation through chromosome oscillation, together with Hec1-S69 phosphorylation, ensures mitotic fidelity by eliminating erroneous kinetochore–microtubule attachments. Attenuated chromosome oscillation and the resulting reduced Hec1-S55 phosphorylation may be a cause of CIN in cancer cell lines.

scholarly journals Meiosis and Kinetochore genes are used by cancer cells as genome destabilizers and transformation catalysts

2019 ◽  
Author(s):  
Roshina Thapa ◽  
Swetha Vasudevan ◽  
Mimi Abo-Ayoub Ashqar ◽  
Eli Reich ◽  
Nataly Kravchenko-Balasha ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Genome Instability ◽  
Chromosome Instability ◽  
Information Theoretic ◽  
Cancer Types ◽  
Altered Gene ◽  
The Relationship ◽  
Hct116 Cells

AbstractCancer cells have an altered transcriptome which contributes to their altered behaviors compared to normal cells. Indeed, many tumors express high levels of genes participating in meiosis or kinetochore biology, but the role of this high expression has not been fully elucidated. In this study we explore the relationship between this overexpression and genome instability and transformation capabilities of cancer cells. For this, we obtained expression data from 5 different cancer types which were analyzed using computational information-theoretic analysis. We were able to show that highly expressed meiotic/kinetochore genes were enriched in the altered gene expression subnetworks characterizing unstable cancer types with high chromosome instability (CIN). However, altered subnetworks found in the cancers with low CIN did not include meiotic and kinetochore genes. Representative gene candidates, found by the analysis to be correlated with a CIN phenotype, were further explored by transfecting genomically-stable (HCT116) and unstable (MCF7) cancer cell lines with vectors overexpressing those genes. This overexpression resulted in an increase in the numbers of abnormal cell divisions and defective spindle formations and in increased transformation properties in stable cancer HCT116 cells. Interestingly, the same properties were less affected by the overexpressed genes in the unstable MCF7 cancer cells. Our results indicate that overexpression of both meiosis and kinetochore genes is capable of driving genomic instability and cancer progression.

Chemotherapy in malignant disease

1970 ◽  
Vol 8 (4) ◽  
pp. 13-16
Keyword(s):  
Cancer Cells ◽  
Cancer Chemotherapy ◽  
Anticancer Agents ◽  
Antimicrobial Chemotherapy ◽  
Malignant Disease ◽  
Human Cells ◽  
Normal Cells ◽  
Different Types ◽  
Normal Human ◽  
Normal Human Cells

Cancer chemotherapy, unlike antimicrobial chemotherapy, is not based on absolute metabolic differences between cancer cells and normal human cells. Anticancer agents inhibit the growth of cells, whether normal or malignant, though different types of cell vary in their susceptibility to these agents, and in their capacity for recovery. The usefulness of these drugs is thus limited by their effects on normal cells.

scholarly journals TAO1 kinase maintains chromosomal stability by facilitating proper congression of chromosomes

Open Biology ◽  
2014 ◽  
Vol 4 (6) ◽  
pp. 130108 ◽  
Author(s):  
Roshan L. Shrestha ◽  
Naoka Tamura ◽  
Anna Fries ◽  
Nicolas Levin ◽  
Joanna Clark ◽  
...  
Keyword(s):  
Error Correction ◽  
Chromosomal Instability ◽  
Spindle Checkpoint ◽  
Human Cells ◽  
Microtubule Dynamics ◽  
Regulatory Pathways ◽  
Chromosomal Stability ◽  
Microtubule Attachment ◽  
Drug Treatments

Chromosomal instability can arise from defects in chromosome–microtubule attachment. Using a variety of drug treatments, we show that TAO1 kinase is required for ensuring the normal congression of chromosomes. Depletion of TAO1 reduces the density of growing interphase and mitotic microtubules in human cells, showing TAO1's role in controlling microtubule dynamics. We demonstrate the aneugenic nature of chromosome–microtubule attachment defects in TAO1-depleted cells using an error-correction assay. Our model further strengthens the emerging paradigm that microtubule regulatory pathways are important for resolving erroneous kinetochore–microtubule attachments and maintaining the integrity of the genome, regardless of the spindle checkpoint status.

scholarly journals The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells

Oncogene ◽  
2020 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Karoline Pudelko ◽  
Jan-Eric Boekenkamp ◽  
Katharina Berger ◽  
Maik Kschischo ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Chromosomal Instability ◽  
Target Gene ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Microtubule Assembly ◽  
Cdk Inhibitor ◽  
Human Cancer Cells

Abstract Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.

scholarly journals A novel role of DNA polymerase λ in translesion synthesis in conjunction with DNA polymerase ζ

2021 ◽  
Vol 4 (4) ◽  
pp. e202000900
Author(s):  
Jung-Hoon Yoon ◽  
Debashree Basu ◽  
Karthi Sellamuthu ◽  
Robert E Johnson ◽  
Satya Prakash ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Dna Polymerase ◽  
Translesion Synthesis ◽  
Dna Lesions ◽  
Human Cells ◽  
Genome Integrity ◽  
Normal Cells ◽  
Normal Human ◽  
Dna Polymerase Λ

By extending synthesis opposite from a diverse array of DNA lesions, DNA polymerase (Pol) ζ performs a crucial role in translesion synthesis (TLS). In yeast and cancer cells, Rev1 functions as an indispensable scaffolding component of Polζ and it imposes highly error-prone TLS upon Polζ. However, for TLS that occurs during replication in normal human cells, Rev1 functions instead as a scaffolding component of Pols η, ι, and κ and Rev1-dependent TLS by these Pols operates in a predominantly error-free manner. The lack of Rev1 requirement for Polζ function in TLS in normal cells suggested that some other protein substitutes for this Rev1 role. Here, we identify a novel role of Polλ as an indispensable scaffolding component of Polζ. TLS studies opposite a number of DNA lesions support the conclusion that as an integral component, Polλ adapts Polζ-dependent TLS to operate in a predominantly error-free manner in human cells, essential for genome integrity and cellular homeostasis.

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