Fueling Genome Maintenance: On the Versatile Roles of NAD in Preserving DNA Integrity

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2022 May 20

PMID 35595095

Authors

Joanna A Ruszkiewicz

Alexander Burkle

Aswin Mangerich

Affiliations

Soon will be listed here.

Abstract

NAD is a versatile biomolecule acting as a master regulator and substrate in various cellular processes, including redox regulation, metabolism, and various signaling pathways. In this article, we concisely and critically review the role of NAD in mechanisms promoting genome maintenance. Numerous NAD-dependent reactions are involved in the preservation of genome stability, the cellular DNA damage response, and other pathways regulating nucleic acid metabolism, such as gene expression and cell proliferation pathways. Of note, NAD serves as a substrate to ADP-ribosyltransferases, sirtuins, and potentially also eukaryotic DNA ligases, all of which regulate various aspects of DNA integrity, damage repair, and gene expression. Finally, we critically analyze recent developments in the field as well as discuss challenges associated with therapeutic actions intended to raise NAD levels.

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References

Luna A, Aladjem M, Kohn K . SIRT1/PARP1 crosstalk: connecting DNA damage and metabolism. Genome Integr. 2013; 4(1):6. PMC: 3898398. DOI: 10.1186/2041-9414-4-6. View

Szanto M, Brunyanszki A, Kiss B, Nagy L, Gergely P, Virag L . Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein. Cell Mol Life Sci. 2012; 69(24):4079-92. PMC: 11114944. DOI: 10.1007/s00018-012-1003-8. View

Kugel S, Mostoslavsky R . Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem Sci. 2014; 39(2):72-81. PMC: 3912268. DOI: 10.1016/j.tibs.2013.12.002. View

Spronck J, Bartleman A, Boyonoski A, Kirkland J . Chronic DNA damage and niacin deficiency enhance cell injury and cause unusual interactions in NAD and poly(ADP-ribose) metabolism in rat bone marrow. Nutr Cancer. 2003; 45(1):124-31. DOI: 10.1207/S15327914NC4501_14. View

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

Fons N, Sundaram R, Breuer G, Peng S, McLean R, Kalathil A . PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. Nat Commun. 2019; 10(1):3790. PMC: 6706443. DOI: 10.1038/s41467-019-11732-6. View

Magni G, Amici A, Emanuelli M, Raffaelli N, Ruggieri S . Enzymology of NAD+ synthesis. Adv Enzymol Relat Areas Mol Biol. 1999; 73:135-82, xi. DOI: 10.1002/9780470123195.ch5. View

Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau D, Zavala E . NAD supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A. 2018; 115(8):E1876-E1885. PMC: 5828618. DOI: 10.1073/pnas.1718819115. View

Xie N, Zhang L, Gao W, Huang C, Huber P, Zhou X . NAD metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther. 2020; 5(1):227. PMC: 7539288. DOI: 10.1038/s41392-020-00311-7. View

10.

Tang M, Li Z, Zhang C, Lu X, Tu B, Cao Z . SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair. Sci Adv. 2019; 5(3):eaav1118. PMC: 6436926. DOI: 10.1126/sciadv.aav1118. View

11.

Rulten S, Fisher A, Robert I, Zuma M, Rouleau M, Ju L . PARP-3 and APLF function together to accelerate nonhomologous end-joining. Mol Cell. 2011; 41(1):33-45. DOI: 10.1016/j.molcel.2010.12.006. View

12.

Barnes D, Tomkinson A, Lehmann A, Webster A, Lindahl T . Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell. 1992; 69(3):495-503. DOI: 10.1016/0092-8674(92)90450-q. View

13.

Bock F, Todorova T, Chang P . RNA Regulation by Poly(ADP-Ribose) Polymerases. Mol Cell. 2015; 58(6):959-69. PMC: 4475274. DOI: 10.1016/j.molcel.2015.01.037. View

14.

Haince J, Kozlov S, Dawson V, Dawson T, Hendzel M, Lavin M . Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem. 2007; 282(22):16441-53. DOI: 10.1074/jbc.M608406200. View

15.

Sies H, Jones D . Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020; 21(7):363-383. DOI: 10.1038/s41580-020-0230-3. View

16.

Boehler C, Gauthier L, Mortusewicz O, Biard D, Saliou J, Bresson A . Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proc Natl Acad Sci U S A. 2011; 108(7):2783-8. PMC: 3041075. DOI: 10.1073/pnas.1016574108. View

17.

Wang J, Chen Q, Wang X, Wang Q, Wang Y, Cheng H . Dysregulation of mitochondrial calcium signaling and superoxide flashes cause mitochondrial genomic DNA damage in Huntington disease. J Biol Chem. 2012; 288(5):3070-84. PMC: 3561531. DOI: 10.1074/jbc.M112.407726. View

18.

Matta E, Kiribayeva A, Khassenov B, Matkarimov B, Ishchenko A . Insight into DNA substrate specificity of PARP1-catalysed DNA poly(ADP-ribosyl)ation. Sci Rep. 2020; 10(1):3699. PMC: 7048826. DOI: 10.1038/s41598-020-60631-0. View

19.

Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M . Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol. 2013; 20(3):347-54. PMC: 3897332. DOI: 10.1038/nsmb.2501. View

20.

Belenky P, Christensen K, Gazzaniga F, Pletnev A, Brenner C . Nicotinamide riboside and nicotinic acid riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism. J Biol Chem. 2008; 284(1):158-164. PMC: 2610512. DOI: 10.1074/jbc.M807976200. View