Deoxyribonucleotide metabolism, mutagenesis and cancer

Nature Reviews Cancer

Volumn 15, Issue 9, 2015, Pages 528-539

  Mathews, Christopher K ^a  

^a OREGON STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; DEOXYRIBONUCLEOSIDE TRIPHOSPHATE; DEOXYRIBONUCLEOTIDE; DNA POLYMERASE; NUCLEOSIDE DIPHOSPHATE KINASE; PHOSPHORIBOSYLTRANSFERASE; RIBONUCLEOTIDE REDUCTASE; NR2E3 PROTEIN, HUMAN; ORPHAN NUCLEAR RECEPTOR;

ALLOSTERISM; CANCER CHEMOTHERAPY; CARCINOGENESIS; CELL AGING; CELL CYCLE REGULATION; CELLULAR DISTRIBUTION; DNA SYNTHESIS; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MITOCHONDRIAL DNA REPLICATION; MUTAGENESIS; NUCLEOTIDE METABOLISM; ONCOGENE; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SPONTANEOUS MUTATION; TELOMERE; GENETICS; METABOLISM; NEOPLASMS; PATHOLOGY;

CELL AGING; DEOXYRIBONUCLEOTIDES; HUMANS; MUTAGENESIS; NEOPLASMS; ONCOGENES; ORPHAN NUCLEAR RECEPTORS; TELOMERE;

EID: 84940046996     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3981     Document Type: Review

References (143)

1. Cohen S. S., & Barner H. D. Studies on unbalanced growth in Escherichia coli. Proc. Natl Acad. Sci. USA 40, 885-893 (1954
2. Cohen S. S., Flaks J. G., Barner H. D., Loeb M. R., & Lichtenstein J. The mode of action of 5 fluorouracil and its derivatives. Proc. Natl Acad. Sci. USA 44, 1004-1012 (1958
3. Hitchings G. H. Chemotherapy and comparative biochemistry: G. H. A. Clowes memorial lecture. Cancer Res. 29, 1895-1903 (1969
4. Kunz B. A., et al. Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability. Mutat. Res. 318, 1-64 (1994
5. Meuth M. The molecular basis of mutations induced by deoxyribonucleoside pool imbalances in mammalian cells. Exp. Cell Res. 181, 305-316 (1989
6. Mathews C. K. DNA precursor metabolism and genomic stability. FASEB J. 20, 1300-1314 (2006
7. Bestwick R. K., Moffett G. L., & Mathews C. K. Selective expansion of mitochondrial deoxyribonucleoside triphosphate pools in antimetaboite-treated HeLa cells. J. Biol. Chem. 257, 9300-9304 (1982
8. Rampazzo C., et al. Mitochondrial deoxyribonucleotides, pool sizes, synthesis, and regulation. J. Biol. Chem. 279, 17019-17026 (2004
9. Ferraro P., et al. Mitochondrial deoxynucleotide pools in quiescent fibroblasts. J. Biol. Chem. 280, 24472-24480 (2005
10. Di Noia M. A., et al. The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters. J. Biol. Chem. 289, 33137-33148 (2014
11. Weinberg S. E., & Chandel N. S. Targeting mitochondrial metabolism for cancer therapy. Nat. Chem. Biol. 11, 9-15 (2015
12. Leeds J. M., Slabaugh M. B., & Mathews C. K. DNA precursor pools and ribonucleotide reductase activity: distribution between the nucleus and cytoplasm of mammalian cells. Mol. Cell. Biol. 5, 3443-3450 (1985
13. Poli J., et al. dNTP pools determine fork progression and origin usage under replication stress. EMBO J. 31, 883-894 (2012
14. Nordlund P., & Reichard P. Ribonucleotide reductases. Ann. Rev. Biochem. 75, 681-706 (2006
15. Stubbe J. Ribonucleotide reductases. Adv. Enzymol. 63, 349-419 (1990
16. Tanaka H., et al. A ribonucleotide reductase gene involved in a p53 dependent cell-cycle checkpoint for DNA damage. Nature 404, 42-49 (2000
17. Guittet O., et al. Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells. J. Biol. Chem. 276, 40647-40651 (2001
18. Shao J., et al. In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer Res. 64, 1-6 (2004
19. Bourdon A., et al. Mutation of RRM2B, encoding p53 controlled ribonucleotide reductase (p53R2), causes severe mitochondrial depletion. Nat. Genet. 39, 776-780 (2007
20. Pontarin G., Ferraro P., Bee L., Reichard P., & Bianchi V. Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells. Proc. Natl Acad. Sci. USA 109, 13302-13307 (2012
21. Chimploy K., & Mathews C. K. Mouse ribonucleotide reductase control. Influence of substrate binding upon interactions with allosteric inhibitors. J. Biol. Chem. 276, 7093-7100 (2001
22. Fairman J. W., et al. Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization. Nat. Struct. Mol. Biol. 18, 316-322 (2011
23. Martomo S. A., & Mathews C. K. Effects of biological DNA precursor pool asymmetry upon accuracy of DNA replication in vitro. Mutat. Res. 499, 197-211 (2002
24. Wheeler L. J., & Mathews C. K. Nucleoside triphosphate pool asymmetry in mammalian mitochondria. J. Biol. Chem. 286, 16992-16996 (2011
25. Postel E. H., Berberich S. J., Flint S. J., & Ferrone C. A. Human c myc transcription factor PuF identified as nm23 H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261, 478-481 (1993
26. Postel E. H. Cleavage of DNA by human NM23 H2/nucleoside diphosphate kinase involves formation of a covalent protein-DNA complex. J. Biol. Chem. 274, 22821-22829 (1999
27. Engström Y., & Rozell B. Immunocytochemical evidence for the cytoplasmic localization and differential expression during the cell cycle of the M1 and M2 subunits of mammalian ribonucleotide reductase. EMBO J. 7, 1615-1620 (1988
28. Pontarin G., et al. Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage. Proc. Natl Acad. Sci. USA 105, 17801-17806 (2008
29. Niida H., et al. Essential role of Tip60 dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase. Genes Dev. 24, 333-338 (2010
30. Hu C. M., et al. Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair. Cancer Cell 22, 36-50 (2012
31. MacFarlane A., et al. Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA. J. Biol. Chem. 286, 44015-44022 (2011
32. Anderson D. D., Eom J. Y., & Stover P. J. Competition between sumoylation and ubiquitination of serine hydroxymethyltransferase 1 determines its nuclear localization and its accumulation in the nucleus. J. Biol. Chem. 287, 4790-4799 (2012
33. Anderson D. D., Woeller C. F., Chiang E. P., Shane B., & Stover P. J. Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis. J. Biol. Chem. 287, 7051-7062 (2012
34. Field M. S., et al. Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. J. Biol. Chem. 289, 29642-29650 (2014
35. Field M. S., Kamynina E., Watkins D., Rosenblatt D. S., & Stover P. J. Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proc. Natl Acad. Sci. USA 112, 400-405 (2015
36. Chabes A. L., Björklund S., & Thelander L. S. Phase-specific transcription of the mouse ribonucleotide reductase R2 gene requires both a proximal repressive EF2 binding site and an upstream promoter activating region. J. Biol. Chem. 279, 10796-10807 (2004
37. Zhang Y. W., et al. Implication of checkpoint kinase-dependent up regulation of ribonucleotide reductase R2 in DNA damage response. J. Biol. Chem. 284, 18085-18095 (2009
38. Salguero I., et al. Ribonucleotide reductase activity is coupled to DNA synthesis via proliferating cell nuclear antigen. Curr. Biol. 22, 720-726 (2012
39. Chabes A., & Thelander L. Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks. J. Biol. Chem. 275, 17747-17753 (2000
40. Bianchi V., et al. Cell cycle-dependent metabolism of pyrimidine deoxynucleoside triphosphates in CEM cells. J. Biol. Chem. 272, 16118-16124 (1997
41. Rampazzo C., et al. Regulation by degradation, a cellular defense against deoxyribonucleotide pool imbalances. Mut. Res. 703, 2-10 (2010
42. Tzoneva G., et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nature Med. 19, 368-371 (2013
43. Powell R. D., Holland P. J., Hollis T., & Perrino F. W. Aicardi-Goutières syndrome gene and HIV 1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase. J. Biol. Chem. 286, 43596-43600 (2011
44. Goldstone D. C., et al. HIV 1 restriction factor SAMHD1 is a deoxynucleotide triphosphohydrolase. Nature 480, 379-382 (2011
45. Laguette N., et al. SAMHD1 is the dendritic and myeloid-cell-specific HIV 1 restriction factor counteracted by Vpx. Nature 474, 654-657 (2011
46. Clifford R., et al. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood 123, 1021-1031 (2014
47. Rossi D. SAMHD1: a new gene for CLL. Blood 123, 951-952 (2014
48. Amie S. M., Bambara R. A., & Kim B. GTP is the primary activator of the anti-HIV restriction factor SAMHD1. J. Biol. Chem. 288, 25001-25006 (2013
49. Koharudin L. M. I., et al. Structural basis of allosteric activation of SAMHD1 by nucleoside triphosphates. J. Biol. Chem. 289, 32617-32627 (2014
50. Ji X., Tang C., Zhao Q., Wang W., & Xiong Y. Structural basis of cellular dNTP regulation by SAMHD1. Proc. Natl Acad. Sci. USA 111, E4305-E4314 (2014
51. Franzolin E., et al. The deoxynucleotide triphosphohydrolase SAMDH1 is a major regulator of DNA precursor pools in mammalian cells. Proc. Natl Acad. Sci. USA 110, 14272-14277 (2013
52. Miazzi C., et al. Allosteric regulation of the human and mouse deoxyribonucleotide triphospholydrolase SAMHD1. J. Biol. Chem. 289, 18339-18346 (2014
53. Hansen E. C., Seamon K. J., Cravens C. N., & Stivers J. T. GTP activator and dNTP substrates of HIV 1 restriction factor SAMHD1 generate a long-lived activated state. Proc. Natl Acad. Sci. USA 111, E1843-E1851 (2014
54. Ryoo J., et al. The ribonuclease activity of SAMHD1 is required for HIV 1 restriction. Nat. Med. 20, 936-941 (2014
55. Loeb L. A., Springgate C. F., & Battula N. Errors in DNA replication as a basis of malignant change. Cancer Res. 34, 2311-2321 (1974
56. Sjöblom T., et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-274 (2006
57. Bielas J. H., Loeb K. R., Rubin B. P., True L. D., & Loeb L. A. Human cancers express a mutator phenotype. Proc. Natl Acad. Sci. USA 103, 18238-18242 (2006
58. Tomasetti C., Marchionni L., Nowak M. A., Parmigiani V., & Vogelstein B. Only three driver mutations are required for the development of lung and colorectal cancers. Proc. Natl Acad. Sci. USA 112, 118-123 (2015
59. Kennedy S. R., et al. Volatility of mutator phenotypes at single cell resolution. PLOS Genet. 11, e1005151 (2015
60. Tomasetti C., & Vogelstein B. Variations in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81 (2015
61. Kumar D., et al. Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Res. 39, 1360-1371 (2010
62. Ahluwalia D., Bienstock R., & Schaaper R. Novel mutator mutants of E. coli ribonucleotide reductase: insights into allosteric regulation and control of mutation rates. DNA Repair 11, 480-487 (2012
63. Buckland R. J., et al. Increased and imbalanced dNTP pools symmetrically promote both leading and lagging strand infidelity. PLOS Genet. 10, e10004846 (2014
64. Kunkel T. A., & Burgers P. M. Dividing the workload at a eukaryotic replication fork. Trends Cell Biol. 18, 521-527 (2008
65. Johansson E., & MacNeill S. A. The eukaryotic replicative DNA polymerases take shape. Trends Biochem. Sci. 35, 339-347 (2010
66. St. Charles J. A., Liberti S. E., Williams J. S., Lujan S. A., & Kunkel T. A. Quantifying the contributions of base selectivity, proofreading and mismatch repair to nuclear DNA replication in Saccharomyces cerevisiae. DNA Repair 31, 41-51 (2015
67. Supek F., & Lehner B. Differential mismatch repair underlies mutation rate variation across the human genome. Nature 521, 81-84 (2015
68. Chabes A., et al. Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase. Cell 112, 391-401 (2003
69. Wheeler L. J., Rajagopal I., & Mathews C. K. Stimulation of mutagenesis by proportional deoxyribonucleoside triphosphate accumulation in Escherichia coli. DNA Repair 4, 1450-1456 (2005
70. Davidson M. B., et al. Endogenous replication stress results in expansion of dNTP pools and a mutator phenotype. EMBO J. 31, 895-907 (2012
71. Gon S., Napolitano R., Rocha W., Coulton S., & Fuchs R. P. Increase in dNTP pool size during the DNA damage response plays a key role in spontaneous and induced mutagenesis in Escherichia coli. Proc. Natl Acad. Sci. USA 108, 19311-19316 (2011
72. Bester A. C., et al. Nucleotide deficiency promotes genomic instability in early stage of cancer development. Cell 145, 435-446 (2011
73. Fearon E. R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 6, 479-507 (2011
74. Church D. N., et al. DNA polymerase e and δ exonuclease domains in endometrial cancer. Hum. Mol. Genet. 22, 2820-2828 (2013
75. Palles C., et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose toward colorectal adenomas and carcinomas. Nat. Genet. 45, 136-144 (2012
76. Mertz T. M., Sharma S., Chabes A., & Shcherbakova P. V. A colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity. Proc. Natl Acad. Sci. USA 112, E2467-E2476 (2015
77. Williams L. N., et al. dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase e variants. Proc. Natl Acad. Sci. USA 112, E2457-E2466 (2015
78. Chabes A., & Stillman B. Constitutively high dNTP concentration inhibits cell cycle progression and the DNA damage checkpoint in yeast Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 104, 1183-1188 (2007
79. Sanvisens N., et al. Yeast Dun1 kinase regulates ribonucleotide reductase inhibitor Sml1 in response to iron deficiency. Mol. Cell. Biol. 34, 3259-3271 (2014
80. Aye Y., Li M., Long M. U. C., & Weiss R. S. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies. Oncogene 34, 2011-2021 (2014
81. Xu X., et al. Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms. Cancer Res. 68, 2652-2660 (2008
82. Taricani L., Shanahan F., Malinao M. C., & Parry D. A functional approach reveals a genetic and physical interaction between ribonucleotide reductase and CHK1 in mammalian cells. PLoS ONE 9, e111714 (2014
83. Åkerblom L., et al. Overproduction of the free radical of ribonucleotide reductase in hydroxyurea-resistant mouse fibroblast 3T6 cells. Proc. Natl Acad. Sci. USA 78, 2159-2163 (1981
84. Wang J., Lohman G. J. S., & Stubbe J. Mechanism of inactivation of human ribonucleotide reductase with p53R2 by gemcitabine 5′ diphosphate. Biochemistry 48, 11612-11621 (2009
85. Artin E., et al. Insight into the mechanism of inactivation of ribonucleotide reductase by gemcitabine 5′ diphosphate in the presence and absence of reductant. Biochemistry 48, 11622-11629 (2009
86. Aye Y., & Stubbe J. Clofarabine 5′ di-and -triphosphates inhibit human ribonucleotide reductase by altering the quaternary structure of its large subunit. Proc. Natl Acad. Sci. USA 108, 9815-9820 (2011
87. Chen M. C., et al. The novel ribonucleotide reductase inhibitor COH29 inhibits DNA repair in vitro. Mol. Pharmacol. 87, 996-1005 (2015
88. Zhao X., Chabes A., Domkin V., Thelander L., & Rothstein R. The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage. EMBO J. 20, 3544-3553 (2001
89. Zhao X., & Rothstein R. The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1. Proc. Natl Acad. Sci. USA 99, 3746-3751 (2002
90. Tsaponina O., Barsoum E., Åström S. U., & Chabes A. Ixr1 is required for the expression of the ribonucleotide reductase Rnr1 and maintenance of dNTP pools. PLOS Genet. 7, e1002061 (2011
91. Kumar D., Viberg J., Nilsson A. K., & Chabes A. Highly mutagenic and severely unbalanced dNTP pool can escape detection by the S phase checkpoint. Nucleic Acids Res. 38, 3975-3983 (2010
92. Tsaponina O., & Chabes A. Pre-activation of the genome integrity checkpoint increases DNA damage tolerance. Nucleic Acids Res. 41, 10371-10378 (2013
93. Angus S. P., et al. Retinoblastoma tumor suppressor targets dNTP metabolism to regulate DNA replication. J. Biol. Chem. 277, 44376-44384 (2002
94. Mannava S., et al. Direct role of nucleotide metabolism in c Myc-dependent proliferation of melanoma cells. Cell Cycle 7, 2392-2400 (2008
95. Cunningham J. T., Moreno M. V., Lodi A., Ronen S. M., & Ruggiero D. Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157, 1008-1103 (2014
96. Mannava S., et al. Depletion of deoxyribonucleotide pools is an endogenous source of DNA damage in cells undergoing oncogene-induced senescence. Am. J. Pathol. 182, 142-150 (2013
97. Mannava S., et al. Ribonucleotide reductase and thymidylate synthase or exogenous deoxyribonucleosides reduce DNA damage and senescence caused by C MYC depletion. Aging 4, 917-922 (2012
98. Aird K. M., et al. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Rep. 3, 1252-1265 (2013
99. Aird K. M., & Zhang R. Nucleotide metabolism, oncogene-induced senescence, and cancer. Cancer Lett. 356, 204-210 (2015
100. Marusyk A., Wheeler L. J., Mathews C. K., & DeGregori J. D. p53 mediates senescence-like arrest induced by chronic replication stress. Mol. Cell. Biol. 27, 5336-5351 (2007
101. Acosta J. C., & Gil J. Senescence: a new weapon for cancer therapy. Trends Cell Biol. 22, 211-219 (2012
102. Saldivar J. C., et al. Initiation of genome instability and preneoplastic processes through loss of Fhit expression. PLOS Genet. 8, e1003077 (2012
103. Xie M., et al. Bcl2 induces replication stress by inhibiting ribonucleotide reductase. Cancer Res. 74, 212-223 (2014
104. Jain D., & Cooper J. P. Telomeric strategies: means to an end. Ann. Rev. Genet. 44, 243-269 (2010
105. Greider C. W., & Blackburn E. H. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337, 331-337 (1989
106. Hornsby P. J. Telomerase and the aging process. Exp. Gerontol. 42, 575-581 (2007
107. Blackburn E. H. Telomerase and cancer. Mol. Cancer Res. 3, 477-482 (2005
108. Maine I. P., Chen F. S., & Windle B. Effect of dGTP concentration on human and CHO telomerase. Biochemistry 38, 15325-15332 (1999
109. Gupta A., et al. Telomere length homeostasis responds to changes in intracellular dNTP pools. Genetics 193, 1095-1105 (2013
110. Friedberg E., et al. in DNA Repair and Mutagenesis 2nd edn 17-25 (ASM Press, 2006
111. Topal M. D., & Baker M. S. DNA precursor pool: a significant target for N methyl-N nitrosourea in CH3/T101/2 clone 8 cells. Proc. Natl Acad. Sci. USA 79, 2211-2215 (1982
112. Maki H., & Sekiguchi M. MutT protein specifically hydrolyzes a potent mutagenic substrate for DNA synthesis. Nature 355, 273-275 (1992
113. Kamiya H. Mutations caused by oxidized DNA precursors and their prevention by nucleotide pool sanitization enzymes. Genes Environ. 29, 133-140 (2007
114. Mao J. Y., Maki H., & Sekiguchi M. Hydrolytic elimination of a mutagenic nucleotide, 8 oxodGTP, by human 18 kilodalton protein: sanitization of nucleotide pool. Proc. Natl Acad. Sci. USA 89, 11021-11025 (1992
115. Sakai Y., et al. A molecular basis for the selective recognition of 2 hydroxy-dATP and 8 oxo-dGTP by human MTH 1. J. Biol. Chem. 277, 8579-8587 (2002
116. Yoshimura D., et al. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J. Biol. Chem. 278, 37965-37973 (2003
117. Takagi Y., et al. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates. J. Biol. Chem. 287, 21541-21549 (2012
118. Tsuzuki T., et al. Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8 oxo-dGTPase. Proc. Natl Acad. Sci. USA 98, 11456-11461 (2001
119. Sakumi K., et al. Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption. Cancer Res. 63, 902-905 (2003
120. Tassotto M. L., & Mathews C. K. Assessing the metabolic function of the MutT 8 oxodeoxyguanosine triphosphatase in Escherichia coli by nucleotide pool analysis. J. Biol. Chem. 277, 15807-15812 (2002
121. Pursell Z. F., McDonald J. T., Mathews C. K., & Kunkel T. A. Trace amounts of 8 oxo-dGTP in mitochondrial extracts reduce DNA polymerase γ replication fidelity. Nucleic Acids Res. 36, 4990-4995 (2008
122. Nakabeppu Y., Kajitani K., Sakamoto K., Yamaguchi H., & Tsuchimoto D. MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. DNA Repair 5, 761-772 (2006
123. Nagy G. N., Leveles I., & Vértessy B. G. Preventive DNA repair by sanitizing the cellular (deoxy) nucleoside triphosphate pool. FEBS J. 281, 4207-4223 (2014
124. Gad H., et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 508, 215-221 (2014
125. Huber K. V. M., et al. Stereospecific targeting of MTH1 by S-crizotinib as an anticancer strategy. Nature 508, 222-226 (2014
126. Heidelberger C. Chemical carcinogenesis, chemotherapy: cancers continuing core challenges - G. H. A. Clowes memorial lecture. Cancer Res. 30, 1549-1569 (1970
127. Carreras C., & Santi D. V. The catalytic mechanism and structure of thymidylate synthase. Annu. Rev. Biochem. 64, 721-762 (1995
128. Curtin N. J., Harris A. L., & Aherne G. W. Mechanism of cell death following thymidylate synthase inhibition: 2′ deoxyuridine 5′ triphosphate accumulation, DNA damage, and growth inhibition following exposure to CB3717 and dipyridamole. Cancer Res. 51, 2346-2352 (1991
129. Parker J. B., & Stivers J. T. Dynamics of uracil and 5 fluorouracil in DNA. Biochemistry 50, 612-617 (2011
130. Miyahara S., et al. Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors. J. Med. Chem. 55, 2970-2980 (2012
131. Longley D. B., Harkin D. P., & Johnston P. G. 5 fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330-338 (2003
132. Doong S. L., & Dolnick B. J. 5 fluorouracil substitution alters pre-mRNA splicing in vitro. J. Biol. Chem. 263, 4467-4473 (1988
133. Yoo B. K., et al. Identification of genes conferring resistance to 5 fluorouracil. Proc. Natl Acad. Sci. USA 106, 12938-12943 (2009
134. Chabner B. A., et al. in Goodman, & Gilmans Pharmacological Basis of Therapeutics 12th edn (eds Brunton L. L., et al.) 1677-1730 (McGraw-Hill, 2011
135. Itsko M., & Schaaper R. M. dGTP starvation in Escherichia coli provides new insights into the thymineless-death phenomenon. PLOS Genet. 10, e1004310 (2014
136. Cannazza G., et al. Internalization and stability of a thymidylate synthase peptide inhibitor in ovarian cancer cells. J. Med. Chem. 57, 10551-10556 (2014
137. Tochowitz A., et al. Alanine mutants of the interface residues of human thymidylate synthase decode key features of the binding mode of allosteric anticancer peptides. J. Med. Chem. 58, 1012-1018 (2014
138. Salo-Ahen O. M. H., et al. Hotspots in an obligate homodimeric anticancer target. Structural and functional effects of interfacial mutations in human thymidylate synthase. J. Med. Chem. 58, 3572-3581 (2015
139. Farber S., et al. Temporary remissions in acute leukemia of children produced by folic acid antagonist, 4 aminopteroyl-glutamic acid (aminopterin). N. Engl. J. Med. 239, 779-787 (1948
140. Osborn M. J., Freeman M., & Huennekens F. M. Inhibition of dihydrofolic reductase by aminopterin and amethopterin. Proc. Soc. Exp. Biol. Med. 97, 429-431 (1958
141. Reichard P., Baldesten A., & Rutberg L. Formation of deoxycytidine phosphates from cytidine phosphates in extracts from Escherichia coli. J. Biol. Chem. 236, 1150-1155 (1961
142. Fersht A. R. Fidelity of replication of phage FX174 by DNA polymerase III holoenzyme: spontaneous mutation by misincorporation. Proc. Natl Acad. Sci. USA 76, 4946-4950 (1979
143. Weinberg G., Ullman B., & Martin D. W. Jr. Mutator phenotypes in mammalian cell mutants with distinct biochemical defects and abnormal deoxyribonucleoside triphosphate pools. Proc. Natl Acad. Sci. USA 78, 2447-2451 (1981