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 Dormant Replication Origin Firing Links Replication Stress to Whole Chromosomal Instability in Human Cancer

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

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 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 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.

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

Enhancement of cisplatin sensitivity by NSC109268 in budding yeast and human cancer cells is associated with inhibition of S-phase progression

2010 ◽  
Vol 66 (5) ◽  
pp. 945-952 ◽  
Author(s):  
Dilip Jain ◽  
Nila Patel ◽  
Melanie Shelton ◽  
Alakananda Basu ◽  
Rouel Roque ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Budding Yeast ◽  
Human Cancer ◽  
S Phase ◽  
Human Cancer Cells ◽  
Cisplatin Sensitivity ◽  
Phase Progression

New betulinic acid derivatives induce potent and selective antiproliferative activity through cell cycle arrest at the S phase and caspase dependent apoptosis in human cancer cells

Biochimie ◽  
2011 ◽  
Vol 93 (6) ◽  
pp. 1065-1075 ◽  
Author(s):  
Rita C. Santos ◽  
Jorge A.R. Salvador ◽  
Roldán Cortés ◽  
Gisela Pachón ◽  
Silvia Marín ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Betulinic Acid ◽  
Human Cancer ◽  
S Phase ◽  
Human Cancer Cells ◽  
Cycle Arrest

scholarly journals The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing

2013 ◽  
Vol 42 (2) ◽  
pp. 926-940 ◽  
Author(s):  
R. A. Frum ◽  
S. Singh ◽  
C. Vaughan ◽  
N. D. Mukhopadhyay ◽  
S. R. Grossman ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Origin ◽  
Replication Stress ◽  
S Phase ◽  
Origin Firing ◽  
Checkpoint Response ◽  
Dna Replication Origin ◽  
S Phase Checkpoint

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
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