Camptothecins and Topoisomerase I; A Foot in the Door. Targeting the Genome Beyond Topoisomerase I with Camptothecins and Novel Anticancer Drugs; Importance of DNA Replication, Repair and Cell Cycle Checkpoints

2004 ◽  
Vol 4 (5) ◽  
pp. 429-434 ◽  
Author(s):  
Yves Pommier
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Anticancer Drugs ◽  
Topoisomerase I ◽  
Cell Cycle Checkpoints

Effect of inhibitors of DNA replication on early zebrafish embryos: evidence for coordinate activation of multiple intrinsic cell-cycle checkpoints at the mid-blastula transition

Zygote ◽  
1997 ◽  
Vol 5 (2) ◽  
pp. 153-175 ◽  
Author(s):  
Richard Ikegami ◽  
Alma K. Rivera-Bennetts ◽  
Deborah L. Brooker ◽  
Thomas D. Yager
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Adaptive Response ◽  
Topoisomerase I ◽  
Topoisomerase Ii ◽  
Cell Cycle Checkpoints ◽  
Zebrafish Embryos ◽  
Replication Process ◽  
Inhibition Of Dna Synthesis

SummaryWe address the developmental activation, in the zebrafish embryo, of intrinsic cell-cycle checkpoints which monitor the DNA replication process and progression through the cell cycle. Eukaryotic DNA replication is probably carried out by a multiprotein complex containing numerous enzymes and accessory factors that act in concert to effect processive DNA synthesis (Applegren, N. et al. (1995) J. Cell. Biochem. 59, 91–107). We have exposed early zebrafish embryos to three chemical agents which are predicted to specifically inhibit the DNA polymerase α, topoisomerase I and topoisomerase II components of the DNA replication complex. We present four findings: (1) Before mid-blastula transition (MBT) an inhibition of DNA synthesis does not block cells from attempting to proceed through mitosis, implying the lack of functional checkpoints. (2) After MBT, the embryo displays two distinct modes of intrinsic checkpoint operation. One mode is a rapid and complete stop of cell division, and the other is an ‘adaptive’ response in which the cell cycle continues to operate, perhaps in a ‘repair’ mode, to generate daughter nuclei with few visible defects. (3) The embryo does not display a maximal capability for the ‘adaptive’ response until several hours after MBT, which is consistent with a slow rranscriptional control mechanism for checkpoint activation. (4) The slow activation of checkpoints at MBT provides a window of time during which inhibitors of DNA synthesis will induce cytogenetic lesions without killing the embryo. This could be useful in the design of a deletion-mutagenesis strategy.

scholarly journals Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Andrea Piunti ◽  
Alessandra Rossi ◽  
Aurora Cerutti ◽  
Mareike Albert ◽  
Sriganesh Jammula ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cell Cycle Checkpoints ◽  
Polycomb Proteins

scholarly journals Correlation between DNA synthesis in the second, third and fourth generations of spermatogonia and the occurrence of apoptosis in both spermatogonia and spermatocytes

Reproduction ◽  
2003 ◽  
pp. 661-668 ◽  
Author(s):  
J Blanco-Rodriguez ◽  
C Martinez-Garcia ◽  
A Porras
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Functional Significance ◽  
Tunel Assay ◽  
Seminiferous Epithelium ◽  
Cell Cycle Checkpoints ◽  
Clear Correlation ◽  
Cellular Events ◽  
Dna Strand

In the seminiferous epithelium, both DNA synthesis and apoptosis occur at equivalent stages in various species, with apoptosis taking place mainly at the same stages as DNA replication in the second, third and fourth spermatogonial generations. As preservation of the cellular associations found at these stages may have some functional significance, it is important to determine whether there is a correlation between these cellular events. In this study, pairs of immunoperoxidase-stained adjacent testis sections from rats, mice, rabbits and cats in which either bromodeoxyuridine incorporated into the newly synthesized DNA strand (BrdU labelling) or DNA 3' end labelling of the apoptotic DNA fragments (TUNEL assay) were detected were compared. In addition, both events were analysed in double-labelled sections. These two methods revealed a clear correlation between the occurrence of DNA replication in the second to fourth generations of spermatogonia and most physiological apoptosis taking place in both spermatogonia and spermatocytes in the three different mammalian orders (Rodentia, Lagomorpha and Carnivora). This correlation may result from the synchronization of mitotic spermatogonial and meiotic spermatocyte cell cycle checkpoints operating at these stages.

scholarly journals Human Exonuclease 1 (EXO1) Regulatory Functions in DNA Replication with Putative Roles in Cancer

2018 ◽  
Vol 20 (1) ◽  
pp. 74 ◽  
Author(s):  
Guido Keijzers ◽  
Daniela Bakula ◽  
Michael Petr ◽  
Nils Madsen ◽  
Amanuel Teklu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Replication ◽  
Replication Fork ◽  
Cellular Transformation ◽  
Cell Cycle Checkpoints ◽  
Replication Process ◽  
Exonuclease 1 ◽  
Repair Pathways ◽  
Regulatory Functions

Human exonuclease 1 (EXO1), a 5′→3′ exonuclease, contributes to the regulation of the cell cycle checkpoints, replication fork maintenance, and post replicative DNA repair pathways. These processes are required for the resolution of stalled or blocked DNA replication that can lead to replication stress and potential collapse of the replication fork. Failure to restart the DNA replication process can result in double-strand breaks, cell-cycle arrest, cell death, or cellular transformation. In this review, we summarize the involvement of EXO1 in the replication, DNA repair pathways, cell cycle checkpoints, and the link between EXO1 and cancer.

scholarly journals CDC6: from DNA replication to cell cycle checkpoints and oncogenesis

2007 ◽  
Vol 29 (2) ◽  
pp. 237-243 ◽  
Author(s):  
Luis R. Borlado ◽  
Juan Méndez
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cell Cycle Checkpoints

scholarly journals Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress

2000 ◽  
Vol 14 (15) ◽  
pp. 1886-1898 ◽  
Author(s):  
Robert S. Weiss ◽  
Tamar Enoch ◽  
Philip Leder
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Chromosomal Abnormalities ◽  
Genotoxic Stress ◽  
Eukaryotic Cell ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Genome Damage

The eukaryotic cell cycle is overseen by regulatory mechanisms, termed checkpoints, that respond to DNA damage, mitotic spindle defects, and errors in the ordering of cell cycle events. The DNA replication and DNA damage cell cycle checkpoints of the fission yeastSchizosaccharomyces pombe require the hus1+(hydroxyurea sensitive) gene. To determine the role of the mouse homolog of hus1+ in murine development and cell cycle checkpoint function, we produced a targeted disruption of mouse Hus1. Inactivation of Hus1results in mid-gestational embryonic lethality due to widespread apoptosis and defective development of essential extra-embryonic tissues. DNA damage-inducible genes are up-regulated inHus1-deficient embryos, and primary cells fromHus1-null embryos contain increased spontaneous chromosomal abnormalities, suggesting that loss of Hus1 leads to an accumulation of genome damage. Embryonic fibroblasts lackingHus1 fail to proliferate in vitro, but inactivation ofp21 allows for the continued growth of Hus1-deficient cells.Hus1−/−p21−/−cells display a unique profile of significantly heightened sensitivity to hydroxyurea, a DNA replication inhibitor, and ultraviolet light, but only slightly increased sensitivity to ionizing radiation. Taken together, these results indicate that mouse Hus1 functions in the maintenance of genomic stability and additionally identify an evolutionarily-conserved role for Hus1 in mediating cellular responses to genotoxins.

Cell cycle checkpoints, DNA repair and DNA replication strategies

BioEssays ◽  
1994 ◽  
Vol 16 (1) ◽  
pp. 75-79 ◽  
Author(s):  
C. Stephen Downes ◽  
Adam S. Wilkins
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Replication ◽  
Cell Cycle Checkpoints

scholarly journals Human TopBP1 Ensures Genome Integrity during Normal S Phase

2005 ◽  
Vol 25 (24) ◽  
pp. 10907-10915 ◽  
Author(s):  
Ja-Eun Kim ◽  
Sarah A. McAvoy ◽  
David I. Smith ◽  
Junjie Chen
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Critical Role ◽  
Genotoxic Stress ◽  
S Phase ◽  
Fragile Sites ◽  
Cell Cycle Checkpoints ◽  
Exogenous Dna ◽  
Hydroxyurea Treatment

ABSTRACT Cell cycle checkpoints are essential for maintaining genomic integrity. Human topoisomerase II binding protein 1 (TopBP1) shares sequence similarity with budding yeast Dpb11, fission yeast Rad4/Cut5, and Xenopus Cut5, all of which are required for DNA replication and cell cycle checkpoints. Indeed, we have shown that human TopBP1 participates in the activation of replication checkpoint and DNA damage checkpoints, following hydroxyurea treatment and ionizing radiation. In this study, we address the physiological function of TopBP1 in S phase by using small interfering RNA. In the absence of exogenous DNA damage, TopBP1 is recruited to replicating chromatin. However, TopBP1 does not appear to be essential for DNA replication. TopBP1-deficient cells have increased H2AX phosphorylation and ATM-Chk 2 activation, suggesting the accumulation of DNA double-strand breaks in the absence of TopBP1. This leads to formation of gaps and breaks at fragile sites, 4N accumulation, and aberrant cell division. We propose that the cellular function of TopBP1 is to monitor ongoing DNA replication. By ensuring proper DNA replication, TopBP1 plays a critical role in the maintenance of genomic stability during normal S phase as well as following genotoxic stress.

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