Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Aug 29

PMID 39201738

Authors

Enol Alvarez-Gonzalez

Luisa Maria Sierra

Affiliations

Soon will be listed here.

Abstract

Metabolic changes involving the tricarboxylic acid (TCA) cycle have been linked to different non-metabolic cell processes. Among them, apart from cancer and immunity, emerges the DNA damage response (DDR) and specifically DNA damage repair. The oncometabolites succinate, fumarate and 2-hydroxyglutarate (2HG) increase reactive oxygen species levels and create pseudohypoxia conditions that induce DNA damage and/or inhibit DNA repair. Additionally, by influencing DDR modulation, they establish direct relationships with DNA repair on at least four different pathways. The AlkB pathway deals with the removal of N-alkylation DNA and RNA damage that is inhibited by fumarate and 2HG. The MGMT pathway acts in the removal of O-alkylation DNA damage, and it is inhibited by the silencing of the gene promoter by 2HG and succinate. The other two pathways deal with the repair of double-strand breaks (DSBs) but with opposite effects: the FH pathway, which uses fumarate to help with the repair of this damage, and the chromatin remodeling pathway, in which oncometabolites inhibit its repair by impairing the homologous recombination repair (HRR) system. Since oncometabolites inhibit DNA repair, their removal from tumor cells will not always generate a positive response in cancer therapy. In fact, their presence contributes to longer survival and/or sensitization against tumor therapy in some cancer patients.

References

Fedeles B, Singh V, Delaney J, Li D, Essigmann J . The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond. J Biol Chem. 2015; 290(34):20734-20742. PMC: 4543635. DOI: 10.1074/jbc.R115.656462. View

Merkley E, Metz T, Smith R, Baynes J, Frizzell N . The succinated proteome. Mass Spectrom Rev. 2013; 33(2):98-109. PMC: 4038156. DOI: 10.1002/mas.21382. View

Ni L, Lin Z, Hu S, Shi Y, Jiang Z, Zhao J . Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages. Biochem Pharmacol. 2022; 198:114935. DOI: 10.1016/j.bcp.2022.114935. View

Amaya M, Pollyea D . Targeting the Pathway in Acute Myeloid Leukemia. Clin Cancer Res. 2018; 24(20):4931-4936. DOI: 10.1158/1078-0432.CCR-18-0536. View

Choudhary C, Weinert B, Nishida Y, Verdin E, Mann M . The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014; 15(8):536-50. DOI: 10.1038/nrm3841. View

Fox M, Roberts J . Drug resistance and DNA repair. Cancer Metastasis Rev. 1987; 6(3):261-81. DOI: 10.1007/BF00144267. View

Li Y, Li Y, Liu X, Zhang L, Chen Y, Zhao Q . Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation. Cell Rep. 2022; 38(7):110391. DOI: 10.1016/j.celrep.2022.110391. View

Gill A, Toon C, Clarkson A, Sioson L, Chou A, Winship I . Succinate dehydrogenase deficiency is rare in pituitary adenomas. Am J Surg Pathol. 2014; 38(4):560-6. PMC: 3966922. DOI: 10.1097/PAS.0000000000000149. View

Eales K, Hollinshead K, Tennant D . Hypoxia and metabolic adaptation of cancer cells. Oncogenesis. 2016; 5:e190. PMC: 4728679. DOI: 10.1038/oncsis.2015.50. View

10.

Intlekofer A, Dematteo R, Venneti S, Finley L, Lu C, Judkins A . Hypoxia Induces Production of L-2-Hydroxyglutarate. Cell Metab. 2015; 22(2):304-11. PMC: 4527873. DOI: 10.1016/j.cmet.2015.06.023. View

11.

Zhang Z, Xin S, Gao M, Cai Y . Promoter hypermethylation of MGMT gene may contribute to the pathogenesis of gastric cancer: A PRISMA-compliant meta-analysis. Medicine (Baltimore). 2017; 96(17):e6708. PMC: 5413244. DOI: 10.1097/MD.0000000000006708. View

12.

Rzem R, Vincent M, Van Schaftingen E, Veiga-da-Cunha M . L-2-hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis. 2007; 30(5):681-9. DOI: 10.1007/s10545-007-0487-0. View

13.

Gill A . Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology. 2017; 72(1):106-116. DOI: 10.1111/his.13277. View

14.

Chan S, Thomas D, Corces-Zimmerman M, Xavy S, Rastogi S, Hong W . Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015; 21(2):178-84. PMC: 4406275. DOI: 10.1038/nm.3788. View

15.

Wang Y, Wild A, Turcan S, Wu W, Sigel C, Klimstra D . Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas. Sci Adv. 2020; 6(17):eaaz3221. PMC: 7176409. DOI: 10.1126/sciadv.aaz3221. View

16.

Aravind L, Koonin E . The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol. 2001; 2(3):RESEARCH0007. PMC: 30706. DOI: 10.1186/gb-2001-2-3-research0007. View

17.

Kang W, Suzuki M, Saito T, Miyado K . Emerging Role of TCA Cycle-Related Enzymes in Human Diseases. Int J Mol Sci. 2021; 22(23). PMC: 8657694. DOI: 10.3390/ijms222313057. View

18.

Yang J, Bashkenova N, Zang R, Huang X, Wang J . The roles of TET family proteins in development and stem cells. Development. 2020; 147(2). PMC: 6983710. DOI: 10.1242/dev.183129. View

19.

Collins R, Patel K, Putnam W, Kapur P, Rakheja D . Oncometabolites: A New Paradigm for Oncology, Metabolism, and the Clinical Laboratory. Clin Chem. 2017; 63(12):1812-1820. DOI: 10.1373/clinchem.2016.267666. View

20.

Lehtonen H, Kiuru M, Ylisaukko-Oja S, Salovaara R, Herva R, Koivisto P . Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet. 2005; 43(6):523-6. PMC: 2564537. DOI: 10.1136/jmg.2005.036400. View