Probing Sister Chromatid Exchange Formation with Halogenated Pyrimidines

Rj, DuFrain

doi:10.1007/978-1-4684-4889-4_3

Cited by 4 publications

(4 citation statements)

References 42 publications

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“…The similarity of the structures and stabilities of the oligonucleotides containing T-A and ClU-A base pairs demonstrated here is consistent with the results of studies showing that substantial amounts of CldU can be incorporated into the DNA of replicating cells (11)(12)(13)(14). Substitution with ClU is not overtly toxic but is more subtle in causing chromosomal aberrations (15)(16)(17)(18)(19)(20). The results of this study suggest that once incorporated, ClU can form a fraudulent base pair with adenine, undetected by DNA repair glycosylases.…”

Section: Discussionsupporting

confidence: 89%

“…Similarly, ClU can be incorporated into the DNA of replicating cells ,− . However, ClU has been shown to induce cellular toxicity, cause senescence, and increase the frequency of sister-chromatid exchanges − . It has been proposed that the toxicity might in part be attributed to interference with nucleotide metabolism, which promotes dUTP misincorporation and repair by a mechanism similar to that proposed for FU .…”

Section: Discussionmentioning

confidence: 99%

“…The impact of the replacement of thymine with ClU in duplex DNA is not yet known. Although CldU is incorporated into the DNA of replicating cells, it does induce toxicity, senescence, and sister-chromatid exchanges − . In this paper, we have constructed synthetic oligonucleotides containing ClU residues at a defined position in a self-complementary duplex paired opposite adenine.…”

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confidence: 99%

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Base Pairing Configuration and Stability of an Oligonucleotide Duplex Containing a 5-Chlorouracil-Adenine Base Pair

et al. 2009

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Inflammation-mediated reactive molecules can damage DNA by oxidation and chlorination. The biological consequences of this damage are as yet incompletely understood. In this paper, we have constructed oligonucleotides containing 5-chlorouracil (ClU), one of the known inflammation damage products. The thermodynamic stability, base pairing configuration and duplex conformation of oligonucleotides containing ClU paired opposite adenine have been examined. NMR spectra reveal that the ClU-A base pair adopts a geometry similar to that of the T-A base pair, and the ClU-A containing duplex adopts a normal B-form conformation. The linewidth of the imino proton of the ClU residue is substantially greater than that of the corresponding T imino proton; however, this difference is not attributed to a reduced thermal or thermodynamic stability or to increased proton exchange with solvent. While the NMR studies reveal increased chemical exchange for the ClU imino proton of the ClU-A base pair, the ClU residue is not a target for removal by the Escherichia coli mispaired uracil glycosylase, which senses damage-related helix instability. The results of this study are consistent with previous reports indicating that the DNA of replicating cells can tolerate substantial substitution with CIU. The fraudulent, pseudo-Watson-Crick ClU-A base pair is sufficiently stable to avoid glycosylase removal and, therefore, might constitute a persistent form of cellular DNA damage.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Base Pairing Configuration and Stability of an Oligonucleotide Duplex Containing a 5-Chlorouracil-Adenine Base Pair

et al. 2009

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“…Since the 5-chloro group of ClU is intermediate in size between fluoro and bromo, the biological properties of ClU could overlap with both FU and BrU. While it is known that 5-chloro-2′-deoxyuridine (CldU) added to culture media is metabolized and incorporated into DNA as shown by antibody binding − , CldU induces senescence, toxicity, and sister-chromatid exchanges by as yet unknown mechanisms − .…”

Section: Introductionmentioning

confidence: 99%

Polymerase Incorporation and Miscoding Properties of 5-Chlorouracil

Kim

Darwanto

Theruvathu

et al. 2010

Chem. Res. Toxicol.

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Inflammation-mediated hypochlorous acid (HOCl) can damage DNA, DNA precursors, and other biological molecules, thereby producing an array of damage products such as 5-chlorouracil (ClU). In this study, we prepared and studied 5-chloro-2’-deoxyuridine (CldU) and ClU-containing oligonucleotide templates. We demonstrate that human K-562 cells grown in culture with 10 µM CldU incorporate substantial amounts of CldU without significant toxicity. When in the template, ClU residues pair with dATP, but also with dGTP, in a pH-dependent manner with incorporation by human polymerase β, Avian Myeloblastosis Virus reverse transcriptase (AMV-RT), and Escherichia coli Klenow fragment (exo−) polymerase. The enhanced miscoding of ClU is attributed to the electron-withdrawing 5-chlorine substituent that promotes formation of an ionized ClU-G mispair. When mispaired with G, ClU is targeted for removal by human glycosylases. The formation, incorporation and repair of ClU could promote transition mutations and other forms of heritable DNA damage.

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Evidence that SCEs induced by mutagens do not occur at the same locus in successive cell cycles: Lack of cancellation in three‐way stained CHO chromosomes

Cortés¹,

Daza²,

Piñero³

et al. 1994

Environ and Mol Mutagen

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An approach based on the synchronization of CHO cells after a first cell cycle incorporating a relatively low amount of bromodeoxyuridine (BrdUrd) into DNA, followed by mutagenic treatment and subsequent culture for second and third generations of BrdUrd incorporation for the scoring of sister chromatid exchanges (SCEs) per cell cycle in three-way differentially (TWD) stained chromosomes, has been used to investigate the possible cancellation of SCEs. Cancellation is expected to occur if two mutagen-induced SCEs occur at exactly the same site in subsequent rounds of replication. Lesions in DNA seem to persist and are able to induce SCE throughout two cell cycles after treatment with the three mutagens tested--mitomycin C (MMC), ethyl methanesulfonate (EMS) and ultraviolet (UV) light--though this latter agent was shown as only moderately persistent. Our results seem to indicate that SCEs induced by these mutagens do not take place at the same locus in successive cell generations, as assessed by a lack of SCE cancellation.

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Probing Sister Chromatid Exchange Formation with Halogenated Pyrimidines

Cited by 4 publications

References 42 publications

Base Pairing Configuration and Stability of an Oligonucleotide Duplex Containing a 5-Chlorouracil-Adenine Base Pair

Base Pairing Configuration and Stability of an Oligonucleotide Duplex Containing a 5-Chlorouracil-Adenine Base Pair

Polymerase Incorporation and Miscoding Properties of 5-Chlorouracil

Evidence that SCEs induced by mutagens do not occur at the same locus in successive cell cycles: Lack of cancellation in three‐way stained CHO chromosomes

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