Differential inhibition of the human cell DNA replication complex-associated DNA polymerases by the antimetabolite 1-β-d-arabinofuranosylcytosine triphosphate (ara-CTP)

Han, Suhua; Hickey, Robert J.; Tom, Timothy D.; Wills, Philip; Syväoja, Juhani E.; Malkas, Linda H.

doi:10.1016/s0006-2952(00)00336-1

Cited by 11 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ara-CTP, the active metabolite of ara-C, directly inhibits DNA ligase (Lamballe et al, 1988;Zittoun et al, 1989Zittoun et al, , 1991 and DNA ligasedependent brain NHEJ (Wang et al, 2003). ara-CTP can also be incorporated into newly synthesized DNA and thereby interrupt replication (Gandhi et al, 1997;Ohno et al, 1998;Abdel-Aziz et al, 2000;Han et al, 2000;Wills et al, 2000). DNA-incorporated ara-CTP interferes with the religation activity of topoisomerases (Cline and Osheroff, 1999;Pourquier et al, 2000;Chrencik et al, 2003;Gmeiner et al, 2003) or with transcription factor binding (Zhang and Kiechle, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…By acting as an inhibitor of DNA ligases (Lamballe et al, 1988;Zittoun et al, 1989Zittoun et al, , 1991 and DNA polymerases (Gandhi et al, 1997;Han et al, 2000;Wills et al, 2000), ara-CTP is able to block the processes of DNA recombination and also of DNA replication. The fact that the effects of ara-CTP on CTA consolidation were observed as early as 4 h after training suggested that its effects were related to blockade of DNA recombination, rather than replication and neurogenesis (Wang et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

Colón-Cesario¹,

Wang²,

Ramos³

et al. 2006

J. Neurosci.

View full text Add to dashboard Cite

Genomic recombination requires cutting, processing, and rejoining of DNA by endonucleases, polymerases, and ligases, among other factors. We have proposed that DNA recombination mechanisms may contribute to long-term memory (LTM) formation in the brain. Our previous studies with the nucleoside analog 1-␤-D-arabinofuranosylcytosine triphosphate (ara-CTP), a known inhibitor of DNA ligases and polymerases, showed that this agent blocked consolidation of conditioned taste aversion without interfering with short-term memory (STM). However, because polymerases and ligases are also essential for DNA replication, it remained unclear whether the effects of this drug on consolidation were attributable to interference with DNA recombination or neurogenesis. Here we show, using C57BL/6 mice, that ara-CTP specifically blocks consolidation but not STM of context fear conditioning, a task previously shown not to require neurogenesis. The effects of a single systemic dose of cytosine arabinoside (ara-C) on LTM were evident as early as 6 h after training. In addition, although ara-C impaired LTM, it did not impair general locomotor activity nor induce brain neurotoxicity. Importantly, hippocampal, but not insular cortex, infusions of ara-C also blocked consolidation of context fear conditioning. Separate studies revealed that context fear conditioning training significantly induced nonhomologous DNA end joining activity indicative of DNA ligasedependent recombination in hippocampal, but not cortex, protein extracts. Finally, unlike inhibition of protein synthesis, systemic ara-C did not block reconsolidation of context fear conditioning. Our results support the idea that DNA recombination is a process specific to consolidation that is not involved in the postreactivation editing of memories.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

Colón-Cesario¹,

Wang²,

Ramos³

et al. 2006

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…ara-CTP inhibits DNA ligase activity by blocking the formation of the adenylate complex essential for completion of the DNA joining reaction (Zittoun et al 1991). In addition, ara-CTP is a competitive inhibitor of DNA polymerases ␣ and ␤ and can be incorporated into DNA, resulting in the interruption of DNA synthesis and DNA repair processes (Ohno et al 1988;Wang et al 1990;Gandhi et al 1997;AbdelAziz et al 2000;Han et al 2000). Importantly, DNA polymerase ␤ is a known component of the base excision repair pathway (Idriss et al 2002) and similarly to factors involved in NHEJ and V(D)J recombination, it is required for embryonic neurogenesis in mice (Gao et al 1998;Sugo et al 2000).…”

mentioning

confidence: 99%

The Antimetabolite ara-CTP Blocks Long-Term Memory of Conditioned Taste Aversion

Wang

Ren²,

Perez³

et al. 2003

Learn. Mem.

View full text Add to dashboard Cite

We examined the hypothesis that processes related to DNA recombination and repair are involved in learning and memory. Rats received intracerebroventricular (icv) infusions of the antimetabolite 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP) or its precursor cytosine arabinoside (ara-C) 30 min prior to conditioned taste aversion (CTA) training. Both ara-CTP and ara-C caused significant impairments in long-term memory (LTM) of CTA. Control experiments indicate that the effect of ara-CTP on CTA memory is related to interference with learning. Furthermore, as it was previously demonstrated for the protein synthesis inhibitor anisomycin, ara-CTP had no effect on CTA memory when it was injected 1 h after training. Importantly, although both ara-CTP and anisomycin significantly blocked LTM in the task, short-term memory (STM) measured 1 h after training was not affected by either of the drugs. Finally, ara-CTP had no effect on in vitro transcription, but it did effectively block nonhomologous DNA end joining (NHEJ) activity of brain protein extracts. We suggest that DNA ligase-mediated DNA recombination and repair processes are necessary for the expression of LTM in the brain.

show abstract

“…Cytarabine is a nucleoside analogue that is widely used for the treatment of leukemia. The phosphorylated cytarabine competes with dCTP for incorporation into DNA, resulting in stalling of the replication fork (36). Although the exact nature of the DNA damage generated by cytarabine in stalled replication forks has not been elucidated, DNA replication-mediated DSB may be produced following recruitment of DNA topoisomerase I or II to the replication fork (37).…”

Section: Discussionmentioning

confidence: 99%

Generation of Replication-Dependent Double-Strand Breaks by the Novel N2-G-Alkylator S23906-1

et al. 2006

View full text Add to dashboard Cite

S23906-1, a new DNA alkylating agent that reacts with the exocyclic 2-NH 2 group of guanine residues yielding monofunctional adducts, is currently under clinical evaluation in phase I trials. To investigate the mechanism of action of S23906-1, we compared parental KB-3-1 cells and KB/S23-500 cells that are 15-fold resistant to S23906-1. Cell death induced by 1 Mmol/L S23906-1 in KB-3-1 cells was associated with their irreversible arrest in the G 2 -M phases of the cell cycle followed by apoptosis, whereas a proportion of the resistant KB/S23-500 cells were able to exit from the G 2 arrest and divide, leading to a significantly lower rate of apoptosis. The attenuated apoptotic response was associated with decreased Chk2 protein phosphorylation, indicating that the DNA damage signaling pathways are more potently activated in the sensitive cells. However, similar rates of adduct formation and repair were measured in both cell lines. Exposure to S23906-1 induced a higher formation of DNA breaks, measured by the comet assay, in sensitive cells. In agreement, a histone H2AX phosphorylation assay revealed that S23906-1 induced double-strand breaks (DSB) in a dose-and timedependent manner and that these were more persistent in the parental cells. These DSBs were found mainly in S-phase cells and inhibited by aphidicolin, suggesting that they are DNA replication-mediated DSBs. These results suggest that secondary DNA lesions play an important role in the cytotoxicity of this compound and make histone H2AX phosphorylation an attractive marker for monitoring the efficacy of S23906-1.

show abstract

Differential inhibition of the human cell DNA replication complex-associated DNA polymerases by the antimetabolite 1-β-d-arabinofuranosylcytosine triphosphate (ara-CTP)

Cited by 11 publications

References 21 publications

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

An Inhibitor of DNA Recombination Blocks Memory Consolidation, But Not Reconsolidation, in Context Fear Conditioning

The Antimetabolite ara-CTP Blocks Long-Term Memory of Conditioned Taste Aversion

Generation of Replication-Dependent Double-Strand Breaks by the Novel N2-G-Alkylator S23906-1

Contact Info

Product

Resources

About