scholarly journals The ribonucleotide reductase inhibitor, Sml1, is sequentially phosphorylated, ubiquitylated and degraded in response to DNA damage

2010 ◽  
Vol 38 (19) ◽  
pp. 6490-6501 ◽  
Author(s):  
Bethany L. Andreson ◽  
Amitabha Gupta ◽  
Bilyana P. Georgieva ◽  
Rodney Rothstein
Keyword(s):  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
Ribonucleotide Reductase Inhibitor

scholarly journals Inactivation of Ku-Mediated End Joining Suppresses mec1Δ Lethality by Depleting the Ribonucleotide Reductase Inhibitor Sml1 through a Pathway Controlled by Tel1 Kinase and the Mre11 Complex

2005 ◽  
Vol 25 (23) ◽  
pp. 10652-10664 ◽  
Author(s):  
Yves Corda ◽  
Sang Eun Lee ◽  
Sylvine Guillot ◽  
André Walther ◽  
Julie Sollier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
Nonhomologous End Joining ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Ribonucleotide Reductase Inhibitor ◽  
Kinase Cascade

ABSTRACT RAD53 and MEC1 are essential Saccharomyces cerevisiae genes required for the DNA replication and DNA damage checkpoint responses. Their lethality can be suppressed by increasing the intracellular pool of deoxynucleotide triphosphates. We report that deletion of YKU70 or YKU80 suppresses mec1Δ, but not rad53Δ, lethality. We show that suppression of mec1Δ lethality is not due to Ku−-associated telomeric defects but rather results from the inability of Ku− cells to efficiently repair DNA double strand breaks by nonhomologous end joining. Consistent with these results, mec1Δ lethality is also suppressed by lif1Δ, which like yku70Δ and yku80Δ, prevents nonhomologous end joining. The viability of yku70Δ mec1Δ and yku80Δ mec1Δ cells depends on the ATM-related Tel1 kinase, the Mre11-Rad50-Xrs2 complex, and the DNA damage checkpoint protein Rad9. We further report that this Mec1-independent pathway converges with the Rad53/Dun1-regulated checkpoint kinase cascade and leads to the degradation of the ribonucleotide reductase inhibitor Sml1.

scholarly journals LC–MS/MS assay for the quantitation of the ribonucleotide reductase inhibitor triapine in human plasma

2017 ◽  
Vol 146 ◽  
pp. 154-160 ◽  
Author(s):  
Julia Matsumoto ◽  
Brian F. Kiesel ◽  
Robert A. Parise ◽  
Jianxia Guo ◽  
Sarah Taylor ◽  
...  
Keyword(s):  
Human Plasma ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
Ribonucleotide Reductase Inhibitor

scholarly journals The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro

2015 ◽  
Vol 87 (6) ◽  
pp. 996-1005 ◽  
Author(s):  
Mei-Chuan Chen ◽  
Bingsen Zhou ◽  
Keqiang Zhang ◽  
Yate-Ching Yuan ◽  
Frank Un ◽  
...  
Keyword(s):  
Dna Repair ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
The Novel ◽  
Ribonucleotide Reductase Inhibitor

scholarly journals Short-Term Toxicological Evaluation of Triapine (3-Amino-Pyridine-2-Carboxaldehyde Thiosemicarbazone or 3-AP), a Ribonucleotide Reductase Inhibitor with Potential Antitumor Activity, in Dogs and Rats

2000 ◽  
Vol 19 (2) ◽  
pp. 85-93 ◽  
Author(s):  
King C. Lee ◽  
James W. Noveroske ◽  
Bijan Almassian
Keyword(s):  
Single Dose ◽  
Antitumor Activity ◽  
Blood Cell ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
Clinical Signs ◽  
Once Daily ◽  
Ribonucleotide Reductase Inhibitor ◽  
Microscopic Findings ◽  
Potential Antitumor

The objective of these studies was to evaluate the potential toxicity of Triapine (a ribonucleotide reductase inhibitor with potential antitumor activity) in dogs and rats. Various doses (1–20 mg/kg) of Triapine were administered intravenously (IV), once daily for 1, 3, or 5 consecutive days, to Beagle dogs or Albino Sprague-Dawley rats. Control animals were treated with vehicle, with an amount equivalent to a dose of 20 mg/kg of Triapine. Data collected included body weights, clinical signs, clinical pathology (serum chemistry and hematology), and gross and microscopic pathology. In dogs, the no-observed-adverse-effect level (NOAEL) of Triapine, when administered once daily for 5 consecutive days, was 1 mg/kg. For 5 daily doses at 3 mg/kg, or a single dose at 10 mg/kg, Triapine induced only limited toxicity (emesis and diarrhea, causing inappetence and body weight loss). The intensities/frequencies of the clinical signs were greater when Triapine was administered over 15 minutes than 120 minutes. Ondansetron (an antiemetic agent due to its H2 antagonistic properties) delayed, but did not eliminate, emesis induced by 10 mg/kg of Triapine. In rats, the NOAEL of Triapine, when administered once daily for 5 consecutive days, was not determined. However, when administered once daily for 3 consecutive days, 1 mg/kg was considered the NOAEL. Five to 20 mg/kg of Triapine (and its vehicle) induced a wide-range of toxicity. Toxicity related to the vehicle (as reflected by the similar or greater intensity/frequency of these effects in vehicle-treated rats than Triapine-treated rats) were reduced activity, discolored urine, discolored tails, and the accompanying gross and histopathological findings. Triapine-related effects were mortality; reductions in total protein and albumin levels; reductions in red blood cell, white blood cell, and platelet counts; reductions in body and thymic weights; increases in the liver and lung weights (and the corresponding microscopic findings of these organs); and microscopic findings of the adrenal cortex, testes, bone marrow, and kidney. These effects generally increased in a dose-related manner between 5–15 mg/kg, and leveled off at 15 and 20 mg/kg. Essentially all effects induced by Triapine and/or vehicle had returned, or were returning, to normal during a 30-day recovery period. In conclusion, the NOAEL of Triapine was 1 mg/kg, when administered daily for 5 consecutive days, in dogs. Five daily doses at 3 mg/kg or a single dose at 10 mg/kg Triapine-induced emesis and diarrhea. The toxicity was greater when Triapine was administered over 15 minutes than over 120 minutes. Ondansetron had limited efficacy in attenuating the emetic effects of the high dose (10 mg/kg) of Triapine. In rats, the NOAEL of Triapine was 1 mg/kg when administered once daily for 3 consecutive days. At 5–20 mg/kg, Triapine induced a broad spectrum of toxicological effects, which is consistent with its ribonucleotide reductase inhibitory properties. Essentially all effects induced by Triapine and/or vehicle were reversible within 30 days.

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