Targeting the DNA Damage Response and Repair in Cancer Through Nucleotide Metabolism

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2022 May 18

PMID 35583750

Authors

Thomas Helleday

Sean G Rudd

Affiliations

Soon will be listed here.

Abstract

The exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anticancer strategy. The replication and repair of DNA are dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard of care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2 and SAMHD1. © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Citing Articles

Integration of single-cell transcriptomics and bulk transcriptomics to explore prognostic and immunotherapeutic characteristics of nucleotide metabolism in lung adenocarcinoma.

Zhang K, Wang L, Chen H, Deng L, Hu M, Wang Z Front Genet. 2025; 15():1466249.

PMID: 39845190 PMC: 11750784. DOI: 10.3389/fgene.2024.1466249.

Nuclear Overexpression of SAMHD1 Induces M Phase Stalling in Hepatoma Cells and Suppresses HCC Progression by Interacting with the Cohesin Complex.

Shao J, Wang W, Li S, Yin G, Han L, Wang X Adv Sci (Weinh). 2024; 12(6):e2411988.

PMID: 39679869 PMC: 11809348. DOI: 10.1002/advs.202411988.

A goldilocks computational protocol for inhibitor discovery targeting DNA damage responses including replication-repair functions.

Moiani D, Tainer J Front Mol Biosci. 2024; 11:1442267.

PMID: 39669672 PMC: 11635304. DOI: 10.3389/fmolb.2024.1442267.

Role of MTH1 in oxidative stress and therapeutic targeting of cancer.

Taiyab A, Ashraf A, Sulaimani M, Rathi A, Shamsi A, Hassan M Redox Biol. 2024; 77:103394.

PMID: 39418911 PMC: 11532495. DOI: 10.1016/j.redox.2024.103394.

Deciphering the role of SAMHD1 in endometrial cancer progression.

Qiang P, Chen Y, Shao Y, Deng Q, Xu S, Zhu W Biol Direct. 2024; 19(1):89.

PMID: 39394602 PMC: 11468744. DOI: 10.1186/s13062-024-00525-7.

References

Morris E, Kunzelmann S, Caswell S, Purkiss A, Kelly G, Taylor I . Probing the Catalytic Mechanism and Inhibition of SAMHD1 Using the Differential Properties of R- and S-dNTPαS Diastereomers. Biochemistry. 2021; 60(21):1682-1698. PMC: 8173608. DOI: 10.1021/acs.biochem.0c00944. View

Gad H, Koolmeister T, Jemth A, Eshtad S, Jacques S, Strom C . MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014; 508(7495):215-21. DOI: 10.1038/nature13181. View

Greenwood E, Williamson J, Sienkiewicz A, Naamati A, Matheson N, Lehner P . Promiscuous Targeting of Cellular Proteins by Vpr Drives Systems-Level Proteomic Remodeling in HIV-1 Infection. Cell Rep. 2019; 27(5):1579-1596.e7. PMC: 6506760. DOI: 10.1016/j.celrep.2019.04.025. View

Tsesmetzis N, Paulin C, Rudd S, Herold N . Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism. Cancers (Basel). 2018; 10(7). PMC: 6071274. DOI: 10.3390/cancers10070240. View

Rai P, Young J, Burton D, Giribaldi M, Onder T, Weinberg R . Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. Oncogene. 2010; 30(12):1489-96. DOI: 10.1038/onc.2010.520. View

Ju H, Lu Y, Chen D, Zuo Z, Liu Z, Wu Q . Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. J Natl Cancer Inst. 2018; 111(6):584-596. PMC: 6579745. DOI: 10.1093/jnci/djy160. View

Jemth A, Gustafsson R, Brautigam L, Henriksson L, Vallin K, Sarno A . MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP. Nucleic Acids Res. 2018; 46(20):10888-10904. PMC: 6237811. DOI: 10.1093/nar/gky896. View

Egashira A, Yamauchi K, Yoshiyama K, Kawate H, Katsuki M, Sekiguchi M . Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA Repair (Amst). 2003; 1(11):881-93. DOI: 10.1016/s1568-7864(02)00113-1. View

Mathews C . Deoxyribonucleotide metabolism, mutagenesis and cancer. Nat Rev Cancer. 2015; 15(9):528-39. DOI: 10.1038/nrc3981. View

10.

Hansen E, Seamon K, Cravens S, Stivers J . GTP activator and dNTP substrates of HIV-1 restriction factor SAMHD1 generate a long-lived activated state. Proc Natl Acad Sci U S A. 2014; 111(18):E1843-51. PMC: 4020072. DOI: 10.1073/pnas.1401706111. View

11.

Carreras-Puigvert J, Zitnik M, Jemth A, Carter M, Unterlass J, Hallstrom B . A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family. Nat Commun. 2017; 8(1):1541. PMC: 5688067. DOI: 10.1038/s41467-017-01642-w. View

12.

Warpman Berglund U, Sanjiv K, Gad H, Kalderen C, Koolmeister T, Pham T . Validation and development of MTH1 inhibitors for treatment of cancer. Ann Oncol. 2016; 27(12):2275-2283. DOI: 10.1093/annonc/mdw429. View

13.

Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras A, Ruppen I, Murga M . USP7 is a SUMO deubiquitinase essential for DNA replication. Nat Struct Mol Biol. 2016; 23(4):270-7. PMC: 4869841. DOI: 10.1038/nsmb.3185. View

14.

Goncalves A, Karayel E, Rice G, Bennett K, Crow Y, Superti-Furga G . SAMHD1 is a nucleic-acid binding protein that is mislocalized due to aicardi-goutières syndrome-associated mutations. Hum Mutat. 2012; 33(7):1116-22. DOI: 10.1002/humu.22087. View

15.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

16.

Amie S, Bambara R, Kim B . GTP is the primary activator of the anti-HIV restriction factor SAMHD1. J Biol Chem. 2013; 288(35):25001-25006. PMC: 3757166. DOI: 10.1074/jbc.C113.493619. View

17.

Kadia T, Gandhi V . Nelarabine in the treatment of pediatric and adult patients with T-cell acute lymphoblastic leukemia and lymphoma. Expert Rev Hematol. 2016; 10(1):1-8. PMC: 5578611. DOI: 10.1080/17474086.2017.1262757. View

18.

De Luca G, Ventura I, Sanghez V, Russo M, Ajmone-Cat M, Cacci E . Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1. Aging Cell. 2013; 12(4):695-705. DOI: 10.1111/acel.12094. View

19.

Nilsson R, Jain M, Madhusudhan N, Gustafsson Sheppard N, Strittmatter L, Kampf C . Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014; 5:3128. PMC: 4106362. DOI: 10.1038/ncomms4128. View

20.

Rai P, Onder T, Young J, McFaline J, Pang B, Dedon P . Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence. Proc Natl Acad Sci U S A. 2009; 106(1):169-74. PMC: 2629241. DOI: 10.1073/pnas.0809834106. View