Inhibiting DNA Polymerases As a Therapeutic Intervention Against Cancer

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2017 Dec 5

PMID 29201867

Citations 26

Authors

Anthony J Berdis

Affiliations

Soon will be listed here.

Abstract

Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.

Citing Articles

The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.

Jankovic M, Poon W, Gonzales-Losada C, Vazquez G, Sharif-Askari B, Ding Y Blood Adv. 2024; 8(20):5315-5329.

PMID: 39093953 PMC: 11497402. DOI: 10.1182/bloodadvances.2023011540.

Amoebicidal Effect of COVID Box Molecules against : A Study of Cell Death.

Sifaoui I, Rodriguez-Exposito R, Reyes-Batlle M, Sutak R, Pinero J, Lorenzo-Morales J Pharmaceuticals (Basel). 2024; 17(6).

PMID: 38931475 PMC: 11206913. DOI: 10.3390/ph17060808.

Replication stress as a driver of cellular senescence and aging.

Herr L, Schaffer E, Fuchs K, Datta A, Brosh Jr R Commun Biol. 2024; 7(1):616.

PMID: 38777831 PMC: 11111458. DOI: 10.1038/s42003-024-06263-w.

Large-Scale Machine Learning Analysis Reveals DNA Methylation and Gene Expression Response Signatures for Gemcitabine-Treated Pancreatic Cancer.

Ogunleye A, Piyawajanusorn C, Ghislat G, Ballester P Health Data Sci. 2024; 4:0108.

PMID: 38486621 PMC: 10904073. DOI: 10.34133/hds.0108.

INHAT subunit SET/TAF-Iβ regulates PRC1-independent H2AK119 mono-ubiquitination via E3 ligase MIB1 in colon cancer.

Park J, Kim J, Park J, Kang J, Oh H, Hahm J NAR Cancer. 2023; 5(3):zcad050.

PMID: 37746636 PMC: 10516711. DOI: 10.1093/narcan/zcad050.

References

Kuchta R, Stengel G . Mechanism and evolution of DNA primases. Biochim Biophys Acta. 2009; 1804(5):1180-9. PMC: 2846230. DOI: 10.1016/j.bbapap.2009.06.011. View

Malspeis L, Grever M, Staubus A, Young D . Pharmacokinetics of 2-F-ara-A (9-beta-D-arabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate. Semin Oncol. 1990; 17(5 Suppl 8):18-32. View

Choi J, Kim S, Motea E, Berdis A . Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents. Oncotarget. 2017; 8(25):40804-40816. PMC: 5522278. DOI: 10.18632/oncotarget.17254. View

Koc O, Phillips Jr W, Lee K, Liu L, Zaidi N, Allay J . Role of DNA repair in resistance to drugs that alkylate O6 of guanine. Cancer Treat Res. 1996; 87:123-46. DOI: 10.1007/978-1-4613-1267-3_5. View

Jensen P, Holm B, Sorensen M, Christensen I, Sehested M . In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. Br J Cancer. 1997; 75(6):869-77. PMC: 2063407. DOI: 10.1038/bjc.1997.154. View

Tan X, Zhao M, Pan K, Dong Y, Dong B, Feng G . Frequent mutation related with overexpression of DNA polymerase beta in primary tumors and precancerous lesions of human stomach. Cancer Lett. 2005; 220(1):101-14. DOI: 10.1016/j.canlet.2004.07.049. View

Tseng W, Derse D, Cheng Y, BROCKMAN R, BENNETT Jr L . In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol. 1982; 21(2):474-7. View

Haracska L, Unk I, Johnson R, Johansson E, Burgers P, Prakash S . Roles of yeast DNA polymerases delta and zeta and of Rev1 in the bypass of abasic sites. Genes Dev. 2001; 15(8):945-54. PMC: 312678. DOI: 10.1101/gad.882301. View

Ling H, Boudsocq F, Plosky B, Woodgate R, Yang W . Replication of a cis-syn thymine dimer at atomic resolution. Nature. 2003; 424(6952):1083-7. DOI: 10.1038/nature01919. View

10.

Yang J, Chen Z, Liu Y, Hickey R, Malkas L . Altered DNA polymerase iota expression in breast cancer cells leads to a reduction in DNA replication fidelity and a higher rate of mutagenesis. Cancer Res. 2004; 64(16):5597-607. DOI: 10.1158/0008-5472.CAN-04-0603. View

11.

Ozols R . Gemcitabine and carboplatin in second-line ovarian cancer. Semin Oncol. 2005; 32(4 Suppl 6):S4-8. DOI: 10.1053/j.seminoncol.2005.06.023. View

12.

Chua Y, Cunningham D . Chemotherapy for advanced pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006; 20(2):327-48. DOI: 10.1016/j.bpg.2005.10.003. View

13.

Doublie S, Tabor S, Long A, Richardson C, Ellenberger T . Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 A resolution. Nature. 1998; 391(6664):251-8. DOI: 10.1038/34593. View

14.

Ohashi E, Ogi T, KUSUMOTO R, Iwai S, Masutani C, Hanaoka F . Error-prone bypass of certain DNA lesions by the human DNA polymerase kappa. Genes Dev. 2000; 14(13):1589-94. PMC: 316741. View

15.

Chen Y, Cleaver J, Hatahet Z, Honkanen R, Chang J, Yen Y . Human DNA polymerase eta activity and translocation is regulated by phosphorylation. Proc Natl Acad Sci U S A. 2008; 105(43):16578-83. PMC: 2575462. DOI: 10.1073/pnas.0808589105. View

16.

Parker W, Cheng Y . Inhibition of DNA primase by nucleoside triphosphates and their arabinofuranosyl analogs. Mol Pharmacol. 1987; 31(2):146-51. View

17.

Pence M, Blans P, Zink C, Hollis T, Fishbein J, Perrino F . Lesion bypass of N2-ethylguanine by human DNA polymerase iota. J Biol Chem. 2008; 284(3):1732-40. PMC: 2615510. DOI: 10.1074/jbc.M807296200. View

18.

Berdis A . Mechanisms of DNA polymerases. Chem Rev. 2009; 109(7):2862-79. DOI: 10.1021/cr800530b. View

19.

McCulloch S, Kunkel T . Multiple solutions to inefficient lesion bypass by T7 DNA polymerase. DNA Repair (Amst). 2006; 5(11):1373-83. PMC: 1892196. DOI: 10.1016/j.dnarep.2006.06.003. View

20.

Meresse P, Dechaux E, Monneret C, Bertounesque E . Etoposide: discovery and medicinal chemistry. Curr Med Chem. 2004; 11(18):2443-66. DOI: 10.2174/0929867043364531. View