scholarly journals Human cancer cells utilize mitotic DNA synthesis to resist replication stress at telomeres regardless of their telomere maintenance mechanism

Oncotarget ◽  
2018 ◽  
Vol 9 (22) ◽  
pp. 15836-15846 ◽  
Author(s):  
Özgün Özer ◽  
Rahul Bhowmick ◽  
Ying Liu ◽  
Ian D. Hickson
Keyword(s):  
Dna Synthesis ◽  
Cancer Cells ◽  
Human Cancer ◽  
Replication Stress ◽  
Telomere Maintenance ◽  
Human Cancer Cells ◽  
Maintenance Mechanism

scholarly journals Adenovirus E4orf4 Protein-Induced Death of p53-/- H1299 Human Cancer Cells Follows a G1 Arrest of both Tetraploid and Diploid Cells due to a Failure To Initiate DNA Synthesis

2013 ◽  
Vol 87 (24) ◽  
pp. 13168-13178 ◽  
Author(s):  
L. Cabon ◽  
N. Sriskandarajah ◽  
M. Z. Mui ◽  
J. G. Teodoro ◽  
P. Blanchette ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Cancer Cells ◽  
Human Cancer ◽  
G1 Arrest ◽  
Human Cancer Cells ◽  
Diploid Cells

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 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

scholarly journals Cdc7 Is an Active Kinase in Human Cancer Cells Undergoing Replication Stress

2006 ◽  
Vol 282 (1) ◽  
pp. 208-215 ◽  
Author(s):  
Pierluigi Tenca ◽  
Deborah Brotherton ◽  
Alessia Montagnoli ◽  
Sonia Rainoldi ◽  
Clara Albanese ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Replication Stress ◽  
Human Cancer Cells

scholarly journals Telomerase Reverse Transcriptase Is Required for the Localization of Telomerase RNA to Cajal Bodies and Telomeres in Human Cancer Cells

2008 ◽  
Vol 19 (9) ◽  
pp. 3793-3800 ◽  
Author(s):  
Rebecca L. Tomlinson ◽  
Eladio B. Abreu ◽  
Tania Ziegler ◽  
Hinh Ly ◽  
Christopher M. Counter ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Cancer Cells ◽  
Human Cancer ◽  
Telomere Maintenance ◽  
Cajal Body ◽  
Cajal Bodies ◽  
Telomerase Reverse Transcriptase ◽  
Telomerase Rna ◽  
Human Cancer Cells ◽  
Essential Components

Telomere maintenance by telomerase is critical for the unlimited division potential of most human cancer cells. The two essential components of human telomerase, telomerase RNA (hTR) and telomerase reverse transcriptase (hTERT), are recruited from distinct subnuclear sites to telomeres during S phase. Throughout the remainder of the cell cycle hTR is found primarily in Cajal bodies. The localization of hTR to Cajal bodies and telomeres is specific to cancer cells where telomerase is active and is not observed in primary cells. Here we show that the trafficking of hTR to both telomeres and Cajal bodies depends on hTERT. RNA interference–mediated depletion of hTERT in cancer cells leads to loss of hTR from both Cajal bodies and telomeres without affecting hTR levels. In addition, expression of hTERT in telomerase-negative cells (including primary and ALT cancer cell lines) induces hTR to localize to both sites. Factors that did not stimulate hTR localization in our experiments include increased hTR RNA levels and Cajal body numbers, and expression of SV40 large T antigen and oncogenic Ras. Our findings suggest that the trafficking of telomerase to Cajal bodies and telomeres in cancer cells correlates with and depends on the assembly of the enzyme.

scholarly journals Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells

2003 ◽  
Vol 373 (2) ◽  
pp. 523-529 ◽  
Author(s):  
Jun Hyun KIM ◽  
Joo Hee KIM ◽  
Gun Eui Lee ◽  
Sang Woong KIM ◽  
I. Kwon CHUNG
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Competitive Inhibitor ◽  
Telomerase Activity ◽  
Inhibitory Effect ◽  
Telomere Maintenance ◽  
Chemical Library ◽  
Human Cancer Cells ◽  
Dna And Rna ◽  
Telomerase Inhibitor

Telomere maintenance is essential for the continued proliferation of dividing cells, and is implicated in chromosome stability and cell immortalization. Telomerase activity allows cells to maintain their telomeric DNA and contributes to the indefinite replicative capacity of cancer cells. Telomerase is expressed in most cancer cells, but not in normal somatic cells, suggesting that telomerase is an attractive target for cancer chemotherapy. Here we screened a chemical library for inhibition of human telomerase, and identified 2,3,7-trichloro-5-nitroquinoxaline (TNQX) as a potent inhibitor. TNQX showed a potent inhibitory effect, with 50% inhibition at ~1.4 μM, and did not inhibit DNA and RNA polymerases, including retroviral reverse trancriptase. A series of enzyme kinetic experiments suggested that TNQX is a mixed-type non-competitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate (TS) primer and the dNTPs. Long-term cultivation of the MCF7 cell line with a drug concentration that did not cause acute cytotoxicity resulted in progressive telomere erosion followed by an increased incidence of chromosome abnormalities and induction of the senescence phenotype. The results presented here indicate that TNQX is a highly potent and selective anti-telomerase agent with good potential for further development as a promising anti-cancer agent.

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