Developing a Model of DNA Replication to Be Used for Monte Carlo Calculations That Predict the Sizes and Shapes of Molecules Resulting from DNA Double-Strand Breaks Induced by X Irradiation during DNA Synthesis

1997 ◽  
Vol 148 (5) ◽  
pp. 421
Author(s):  
W. C. Dewey ◽  
N. Albright
Keyword(s):  
Monte Carlo ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Monte Carlo Calculations ◽  
X Irradiation

scholarly journals Tim–Tipin dysfunction creates an indispensible reliance on the ATR–Chk1 pathway for continued DNA synthesis

2009 ◽  
Vol 187 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Kevin D. Smith ◽  
Michael A. Fu ◽  
Eric J. Brown
Keyword(s):  
Dna Synthesis ◽  
Genome Stability ◽  
Double Strand Breaks ◽  
Dna Unwinding ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Nucleotide Incorporation ◽  
Pathway Activation ◽  
Maintain Genome Stability

The Tim (Timeless)–Tipin complex has been proposed to maintain genome stability by facilitating ATR-mediated Chk1 activation. However, as a replisome component, Tim–Tipin has also been suggested to couple DNA unwinding to synthesis, an activity expected to suppress single-stranded DNA (ssDNA) accumulation and limit ATR–Chk1 pathway engagement. We now demonstrate that Tim–Tipin depletion is sufficient to increase ssDNA accumulation at replication forks and stimulate ATR activity during otherwise unperturbed DNA replication. Notably, suppression of the ATR–Chk1 pathway in Tim–Tipin-deficient cells completely abrogates nucleotide incorporation in S phase, indicating that the ATR-dependent response to Tim–Tipin depletion is indispensible for continued DNA synthesis. Replication failure in ATR/Tim-deficient cells is strongly associated with synergistic increases in H2AX phosphorylation and DNA double-strand breaks, suggesting that ATR pathway activation preserves fork stability in instances of Tim–Tipin dysfunction. Together, these experiments indicate that the Tim–Tipin complex stabilizes replication forks both by preventing the accumulation of ssDNA upstream of ATR–Chk1 function and by facilitating phosphorylation of Chk1 by ATR.

scholarly journals Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells

Cell Cycle ◽  
2013 ◽  
Vol 12 (5) ◽  
pp. 773-782 ◽  
Author(s):  
Tsutomu Shimura ◽  
Yasushi Ochiai ◽  
Naoto Noma ◽  
Toshiyuki Oikawa ◽  
Yui Sano ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cyclin D1 ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

Natural Products as Anti-Cancerous Therapeutic Molecules Targeted towards Topoisomerases

2020 ◽  
Vol 21 (11) ◽  
pp. 1103-1142
Author(s):  
Swati Singh ◽  
Veda P. Pandey ◽  
Kusum Yadav ◽  
Anurag Yadav ◽  
U. N. Dwivedi
Keyword(s):  
Dna Replication ◽  
Double Strand Breaks ◽  
Dynamics Simulation ◽  
Present Review ◽  
Cancer Drug ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Therapeutic Molecules ◽  
Topo Ii ◽  
Derivatives Of

: Topoisomerases are reported to resolve the topological problems of DNA during several cellular processes, such as DNA replication, transcription, recombination, and chromatin remodeling. Two types of topoisomerases (Topo I and II) accomplish their designated tasks by introducing single- or double-strand breaks within the duplex DNA molecules, and thus maintain the proper structural conditions of DNA to release the topological torsions, which is generated by unwinding of DNA to access coded information, in the course of replication, transcription, and other processes. Both the topoisomerases have been looked at as crucial targets against various types of cancers such as lung, melanoma, breast, and prostate cancers. Conceptually, targeting topoisomerases will disrupt both DNA replication and transcription, thereby leading to inhibition of cell division and consequently stopping the growth of actively dividing cancerous cells. Since the discovery of camptothecin (an alkaloid) as an inhibitor of Topo I in 1958, a number of derivatives of camptothecin were developed as potent inhibitors of Topo I. Two such derivatives of camptothecin, namely, topotecan and irinotecan, have been commonly used as US Food and Drug Administration (FDA) approved drugs against Topo I. Similarly, the first Topo II inhibitor, namely, etoposide, an analogue of podophyllotoxin, was developed in 1966 and got FDA approval as an anti-cancer drug in 1983. Subsequently, several other inhibitors of Topo II, such as doxorubicin, mitoxantrone, and teniposide, were developed. These drugs have been reported to cause accumulation of cytotoxic non-reversible DNA double-strand breaks (cleavable complex). Thus, the present review describes the anticancer potential of plant-derived secondary metabolites belonging to alkaloids, flavonoids and terpenoids directed against topoisomerases. Furthermore, in view of the recent advances made in the field of computer-aided drug design, the present review also discusses the use of computational approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to assess and predict the safety, efficacy, potency and identification of these potent anti-cancerous therapeutic molecules.

A Role for DNA Double Strand Breaks in the Sensitivity of AML Cells to Clofarabine: Enhanced In Vitro Sensitivity in Primary AML Cells with FLT3 Mutations.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2582-2582
Author(s):  
Monica Pallis ◽  
Martin Grundy ◽  
Claire Seedhouse ◽  
Heather Pimblett ◽  
Nigel Russell
Keyword(s):  
Cell Death ◽  
Dna Synthesis ◽  
Cell Lines ◽  
Mitochondrial Membrane ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Cytochrome C Release ◽  
Strand Breaks ◽  
Flt3 Mutations ◽  
Kg1 Cells

Abstract Clofarabine is a purine nucleoside analogue which has been incorporated into several therapeutic trial protocols for the treatment of leukaemias including acute myeloid leukaemia (AML). The aims of the study are to ascertain mechanisms of clofarabine action in AML using cell lines and presentation samples from patients. We measured apoptosis by TdT assay, cytochrome C release and flow cytometric assays of the mitochondrial membrane potential probe DiOC6. To study the effects of clofarabine on DNA synthesis and DNA double strand breaks, we used bromodeoxyuridine (BrdU) and H2AX assays respectively. Equitoxic doses were established that caused approximately 20% cell death in the AML cell lines HL-60 (0.3 μM), KG1 (1 μM) and MV4.11 (1 μM) after 6 hours of continuous exposure. At these doses, clofarabine induced apoptotic DNA nicks, as measured by the TdT assay, and Cytochrome C release in all three cell lines. However, clofarabine-induced mitochondrial hyperpolarisation and depolarisation were found to be cell-type specific, occurring in HL-60 but not MV4.11 or KG1 cells, i.e. mitochondrial membrane depolarisation is not an essential part of the mechanism of clofarabine-induced apoptosis. Following clofarabine treatment, DNA synthesis was reduced by 91% within 1 hour in KG1 cells and by 80% in HL-60, but by only 9% in MV4.11. Out of the three cell lines, MV4.11 cells, which have a FLT3 internal tandem duplication (ITD), were the only ones to completely repair DNA double strand breaks following clofarabine removal. In 12 samples from patients with AML, the proportion of cells which incorporated BrdU in a 45 minute assay - a measure of the rate of cell cycling - differed considerably between samples, from 0.8% to 23%, median 13%. Cell death induced by clofarabine was correlated with the cycling rate of untreated cells (P=0.016). All 12 samples showed inhibition of DNA synthesis within 60 minutes of clofarabine treatment (range 20%–92% inhibition, median 54%). Mitochondrial membrane hyperpolarisation and depolarisation were not observed in patient cells. However, DNA double strand breaks were induced by clofarabine in patient cells. Paradoxically, i.e. in contrast to the results seen with the MV4.11 cell line, toxicity was greatest in samples with a FLT3 mutation (P=0.007). In conclusion, the FLT3 mutant MV4.11 cell line effectively repairs clofarabine-induced double strand breaks. Cell death in patient cells cultured with clofarabine is correlated with the presence of a FLT3 mutation. As we have previously established that AML samples with FLT3 mutations have upregulated DNA repair activity, this paradox might be explained by cycles of attempted DNA repair frustrated by renewed clofarabine incoporation into DNA, thus increasing the toxicity of the drug.

Chromatin loading of Smc5/6 is induced by DNA replication but not by DNA double-strand breaks

2006 ◽  
Vol 351 (4) ◽  
pp. 935-939 ◽  
Author(s):  
Takashi Tsuyama ◽  
Katsutoshi Inou ◽  
Masayuki Seki ◽  
Takahiko Seki ◽  
Yuji Kumata ◽  
...  
Keyword(s):  
Dna Replication ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks
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