Intracellular Nucleotide Pools and Their Significance in Antimetabolite Therapy1

2015 ◽  
pp. 68-77 ◽  
Author(s):  
K. R. Harrap ◽  
J. Renshaw
Keyword(s):  
Nucleotide Pools

scholarly journals Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joonas A. Jamsen ◽  
Akira Sassa ◽  
Lalith Perera ◽  
David D. Shock ◽  
William A. Beard ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Time Lapse ◽  
Strand Break ◽  
Structural Basis ◽  
End Joining ◽  
Strand Breaks ◽  
Nucleotide Pools ◽  
Nucleotide Insertion ◽  
Non Homologous End Joining

AbstractReactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.

scholarly journals Limited nucleotide pools restrict Epstein–Barr virus-mediated B-cell immortalization

Oncogenesis ◽  
2017 ◽  
Vol 6 (6) ◽  
pp. e349-e349 ◽  
Author(s):  
A Y Hafez ◽  
J E Messinger ◽  
K McFadden ◽  
G Fenyofalvi ◽  
C N Shepard ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Nucleotide Pools ◽  
Cell Immortalization ◽  
Epstein Barr

Alterations in nucleotide pools in rats fed diets deficient in choline, methionine and/or folic acid

1992 ◽  
Vol 13 (12) ◽  
pp. 2471-2474 ◽  
Author(s):  
S.Jill James ◽  
David R. Cross ◽  
Barbara J. Miller
Keyword(s):  
Folic Acid ◽  
Nucleotide Pools

Methotrexate-induced morphological changes mimic those seen after heat shock

1989 ◽  
Vol 92 (1) ◽  
pp. 37-49
Author(s):  
D.A. Jackson ◽  
C.K. Pearson ◽  
D.C. Fraser ◽  
K.M. Prise ◽  
S.Y. Wong
Keyword(s):  
Heat Shock ◽  
Morphological Changes ◽  
Dna Strand Breaks ◽  
Chemotherapeutic Drug ◽  
General Stress Response ◽  
Strand Breaks ◽  
Nucleotide Pools ◽  
Concentration Changes ◽  
High Concentrations ◽  
Dna Strand

The survival of cells cultured in medium containing the chemotherapeutic drug methotrexate (MTX) is related directly to drug concentration. Changes in DNA resulting from a severe imbalance in the cells' nucleotide pools are thought to account for this cytotoxicity. We have attempted to clarify the gross biochemical changes that might lead to cell death. DNA strand breaks occur in cells treated with high concentrations of MTX but it is not clear that these are sufficient to account for cytotoxicity at lower doses. We observed dramatic changes in cytoskeletal morphology. Gross reorganization of the cytoskeleton is shown by immunolabelling but is high-lighted dramatically when cells are lysed to leave ‘nucleoids’. The nature of the changes seen in MTX-treated cells is characteristic of the cells’ general stress response, seen originally following heat shock. This study shows that other factors, such as changes in cytoskeletal function, must be considered together with any contribution from DNA damage, in order to account for the lethal effects of MTX.

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