Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2021 Sep 28

PMID 34572497

Citations 20

Authors

Anzhela V Pavlova

Elena A Kubareva

Mayya V Monakhova

Maria I Zvereva

Nina G Dolinnaya

Affiliations

Soon will be listed here.

Abstract

DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes the results of recent studies of G4-mediated genomic and epigenomic instability, together with associated DNA damage and repair processes. Although the underlying mechanisms remain to be elucidated, it is known that, among the proteins that recognize G4 structures, many are linked to DNA repair. We analyzed the possible role of G4s in promoting double-strand DNA breaks, one of the most deleterious DNA lesions, and their repair via error-prone mechanisms. The patterns of G4 damage, with a focus on the introduction of oxidative guanine lesions, as well as their removal from G4 structures by canonical repair pathways, were also discussed together with the effects of G4s on the repair machinery. According to recent findings, there must be a delicate balance between G4-induced genome instability and G4-promoted repair processes. A broad overview of the factors that modulate the stability of G4 structures in vitro and in vivo is also provided here.

Citing Articles

G-Quadruplex Structures Formed by Human Telomere and GGGGCC Repeats.

Yan B, Suen M, Xu N, Lu C, Liu C, Zhu G Int J Mol Sci. 2025; 26(4).

PMID: 40004056 PMC: 11855686. DOI: 10.3390/ijms26041591.

G-quadruplex structures in 16S rRNA regions correlate with thermal adaptation in prokaryotes.

Lyu B, Niu K, Anderson D, Feng Q, Song Q Nucleic Acids Res. 2025; 53(3).

PMID: 39883013 PMC: 11780868. DOI: 10.1093/nar/gkaf042.

Position-Dependent Effects of AP Sites Within an Promoter G-Quadruplex Scaffold on Quadruplex Stability and Repair Activity of the APE1 Enzyme.

Savitskaya V, Novoselov K, Dolinnaya N, Monakhova M, Snyga V, Diatlova E Int J Mol Sci. 2025; 26(1.

PMID: 39796192 PMC: 11720163. DOI: 10.3390/ijms26010337.

Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain.

Polyzos A, Cheong A, Yoo J, Blagec L, Toprani S, Nagel Z Nat Commun. 2024; 15(1):7726.

PMID: 39231940 PMC: 11375129. DOI: 10.1038/s41467-024-51906-5.

Structural Unfolding of G-Quadruplexes: From Small Molecules to Antisense Strategies.

Fracchioni G, Vailati S, Grazioli M, Pirota V Molecules. 2024; 29(15).

PMID: 39124893 PMC: 11314335. DOI: 10.3390/molecules29153488.

References

Schimmel J, van Schendel R, den Dunnen J, Tijsterman M . Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining. Trends Genet. 2019; 35(9):632-644. DOI: 10.1016/j.tig.2019.06.001. View

Masuda-Sasa T, Imamura O, Campbell J . Biochemical analysis of human Dna2. Nucleic Acids Res. 2006; 34(6):1865-75. PMC: 1428797. DOI: 10.1093/nar/gkl070. View

Koole W, van Schendel R, Karambelas A, van Heteren J, Okihara K, Tijsterman M . A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites. Nat Commun. 2014; 5:3216. DOI: 10.1038/ncomms4216. View

Cui Y, Kong D, Ghimire C, Xu C, Mao H . Mutually Exclusive Formation of G-Quadruplex and i-Motif Is a General Phenomenon Governed by Steric Hindrance in Duplex DNA. Biochemistry. 2016; 55(15):2291-9. DOI: 10.1021/acs.biochem.6b00016. View

Wu C, Spies M . G-quadruplex recognition and remodeling by the FANCJ helicase. Nucleic Acids Res. 2016; 44(18):8742-8753. PMC: 5062972. DOI: 10.1093/nar/gkw574. View

Brazda V, cerven J, Bartas M, Mikyskova N, Coufal J, Pecinka P . The Amino Acid Composition of Quadruplex Binding Proteins Reveals a Shared Motif and Predicts New Potential Quadruplex Interactors. Molecules. 2018; 23(9). PMC: 6225207. DOI: 10.3390/molecules23092341. View

Miclot T, Corbier C, Terenzi A, Hognon C, Grandemange S, Barone G . Forever Young: Structural Stability of Telomeric Guanine Quadruplexes in the Presence of Oxidative DNA Lesions*. Chemistry. 2021; 27(34):8865-8874. DOI: 10.1002/chem.202100993. View

Piazza A, Adrian M, Samazan F, Heddi B, Hamon F, Serero A . Short loop length and high thermal stability determine genomic instability induced by G-quadruplex-forming minisatellites. EMBO J. 2015; 34(12):1718-34. PMC: 4475404. DOI: 10.15252/embj.201490702. View

Fujii T, Podbevsek P, Plavec J, Sugimoto N . Effects of metal ions and cosolutes on G-quadruplex topology. J Inorg Biochem. 2016; 166:190-198. DOI: 10.1016/j.jinorgbio.2016.09.001. View

10.

Fleming A, Zhou J, Wallace S, Burrows C . A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These "Spare Tires" Have an Evolved Function?. ACS Cent Sci. 2015; 1(5):226-233. PMC: 4571166. DOI: 10.1021/acscentsci.5b00202. View

11.

Kolesnikova S, Hubalek M, Bednarova L, Cvacka J, Curtis E . Multimerization rules for G-quadruplexes. Nucleic Acids Res. 2017; 45(15):8684-8696. PMC: 5587800. DOI: 10.1093/nar/gkx637. View

12.

Broxson C, Hayner J, Beckett J, Bloom L, Tornaletti S . Human AP endonuclease inefficiently removes abasic sites within G4 structures compared to duplex DNA. Nucleic Acids Res. 2014; 42(12):7708-19. PMC: 4081060. DOI: 10.1093/nar/gku417. View

13.

Sun D, Hurley L . The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression. J Med Chem. 2009; 52(9):2863-74. PMC: 2757002. DOI: 10.1021/jm900055s. View

14.

Saranathan N, Vivekanandan P . G-Quadruplexes: More Than Just a Kink in Microbial Genomes. Trends Microbiol. 2018; 27(2):148-163. PMC: 7127049. DOI: 10.1016/j.tim.2018.08.011. View

15.

Halabi A, Ditch S, Wang J, Grabczyk E . DNA mismatch repair complex MutSβ promotes GAA·TTC repeat expansion in human cells. J Biol Chem. 2012; 287(35):29958-67. PMC: 3436174. DOI: 10.1074/jbc.M112.356758. View

16.

Omaga C, Fleming A, Burrows C . The Fifth Domain in the G-Quadruplex-Forming Sequence of the Human NEIL3 Promoter Locks DNA Folding in Response to Oxidative Damage. Biochemistry. 2018; 57(20):2958-2970. PMC: 6002760. DOI: 10.1021/acs.biochem.8b00226. View

17.

Redstone S, Fleming A, Burrows C . Oxidative Modification of the Potential G-Quadruplex Sequence in the PCNA Gene Promoter Can Turn on Transcription. Chem Res Toxicol. 2019; 32(3):437-446. PMC: 6422741. DOI: 10.1021/acs.chemrestox.8b00332. View

18.

Laguerre A, Hukezalie K, Winckler P, Katranji F, Chanteloup G, Pirrotta M . Visualization of RNA-Quadruplexes in Live Cells. J Am Chem Soc. 2015; 137(26):8521-5. DOI: 10.1021/jacs.5b03413. View

19.

Onyshchenko M, Gaynutdinov T, Englund E, Appella D, Neumann R, Panyutin I . Quadruplex formation is necessary for stable PNA invasion into duplex DNA of BCL2 promoter region. Nucleic Acids Res. 2011; 39(16):7114-23. PMC: 3167611. DOI: 10.1093/nar/gkr259. View

20.

Takahashi S, Brazier J, Sugimoto N . Topological impact of noncanonical DNA structures on Klenow fragment of DNA polymerase. Proc Natl Acad Sci U S A. 2017; 114(36):9605-9610. PMC: 5594654. DOI: 10.1073/pnas.1704258114. View