G-quadruplexes (G4s) are functional elements of the human genome, some of which inhibit DNA replication. We investigated replication of G4s within highly abundant microsatellite (GGGA, GGGT) and transposable element (L1 and SVA) sequences. We found that genome-wide, numerous motifs are located preferentially on the replication leading strand and the transcribed strand templates. We directly tested replicative polymerase ϵ and δ holoenzyme inhibition at these G4s, compared to low abundant motifs. For all G4s, DNA synthesis inhibition was higher on the G-rich than C-rich strand or control sequence. No single G4 was an absolute block for either holoenzyme; however, the inhibitory potential varied over an order of magnitude. Biophysical analyses showed the motifs form varying topologies, but replicative polymerase inhibition did not correlate with a specific G4 structure. Addition of the G4 stabilizer pyridostatin severely inhibited forward polymerase synthesis specifically on the G-rich strand, enhancing G/C strand asynchrony. Our results reveal that replicative polymerase inhibition at every G4 examined is distinct, causing complementary strand synthesis to become asynchronous, which could contribute to slowed fork elongation. Altogether, we provide critical information regarding how replicative eukaryotic holoenzymes navigate synthesis through G4s naturally occurring thousands of times in functional regions of the human genome.

Department of Biochemistry and Molecular Biology Penn State University College of Medicine Hershey PA 17033 United States

Department of Biology Penn State University Eberly College of Science University Park PA 16802 United States

Department of Biophysics of Nucleic Acids Institute of Biophysics of the Czech Academy of Sciences Brno 61265 Czech Republic

Department of Chemistry Penn State University Eberly College of Science University Park PA 16802 United States

Department of Pathology The Jake Gittlen Laboratories for Cancer Research Penn State University College of Medicine Hershey PA 17033 United States

Department of Plant Developmental Genetics Institute of Biophysics of the Czech Academy of Sciences Brno 61265 Czech Republic

National Institute of Environmental Health Sciences Z01 ES065070 Durham NC 27709 United States

Zobrazit více v PubMed

Tomasetti  C, Li  L, Vogelstein  B  Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science. 2017; 355:1330–4.10.1126/science.aaf9011. PubMed DOI PMC

Hoyt  SJ, Storer  JM, Hartley  GA  et al. .  From telomere to telomere: the transcriptional and epigenetic state of human repeat elements. Science. 2022; 376:eabk3112.10.1126/science.abk3112. PubMed DOI PMC

Guiblet  WM, Cremona  MA, Harris  RS  et al. .  Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome. Nucleic Acids Res. 2021; 49:1497–516.10.1093/nar/gkaa1269. PubMed DOI PMC

López  Castel A, Cleary  JD, Pearson  CE  Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol. 2010; 11:165–70.10.1038/nrm2854. PubMed DOI

Makova  KD, Weissensteiner  MH  Noncanonical DNA structures are drivers of genome evolution. Trends Genet. 2023; 39:109–24.10.1016/j.tig.2022.11.005. PubMed DOI PMC

Usdin  K  The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res. 2008; 18:1011–9.10.1101/gr.070409.107. PubMed DOI PMC

Wang  G, Vasquez  KM  Dynamic alternative DNA structures in biology and disease. Nat Rev Genet. 2023; 24:211–34.10.1038/s41576-022-00539-9. PubMed DOI PMC

Khristich  AN, Mirkin  S  On the wrong DNA track: molecular mechanisms of repeat-mediated genome instability. J Biol Chem. 2020; 295:4134–70.10.1074/jbc.REV119.007678. PubMed DOI PMC

Burge  S, Parkinson  GN, Hazel  P  et al. .  Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 2006; 34:5402–15.10.1093/nar/gkl655. PubMed DOI PMC

Spiegel  J, Adhikari  S, Balasubramanian  S  The structure and function of DNA G-quadruplexes. Trends Chem. 2020; 2:123–36.10.1016/j.trechm.2019.07.002. PubMed DOI PMC

Guiblet  WM, DeGiorgio  M, Cheng  X  et al. .  Selection and thermostability suggest G-quadruplexes are novel functional elements of the human genome. Genome Res. 2021; 31:1136–49.10.1101/gr.269589.120. PubMed DOI PMC

Varshney  D, Spiegel  J, Zyner  K  et al. .  The regulation and functions of DNA and RNA G-quadruplexes. Nat Rev Mol Cell Biol. 2020; 21:459–74.10.1038/s41580-020-0236-x. PubMed DOI PMC

Hänsel-Hertsch  R, Beraldi  D, Lensing  SV  et al. .  G-quadruplex structures mark human regulatory chromatin. Nat Genet. 2016; 48:1267–72.10.1038/ng.3662. PubMed DOI

Huppert  JL, Balasubramanian  S  G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res. 2007; 35:406–13.10.1093/nar/gkl1057. PubMed DOI PMC

Lexa  M, Steflova  P, Martinek  T  et al. .  Guanine quadruplexes are formed by specific regions of human transposable elements. BMC Genomics. 2014; 15:1032.10.1186/1471-2164-15-1032. PubMed DOI PMC

Tokan  V, Rodriguez  Lorenzo JL, Jedlicka  P  et al. .  Quadruplex-forming motif inserted into 3′UTR of Ty1his3-AI retrotransposon inhibits retrotransposition in yeast. Biology. 2021; 10:347. PubMed PMC

Sahakyan  AB, Murat  P, Mayer  C  et al. .  G-quadruplex structures within the 3′ UTR of LINE-1 elements stimulate retrotransposition. Nat Struct Mol Biol. 2017; 24:243–7. PubMed

Bacolla  A, Ye  Z, Ahmed  Z  et al. .  Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction. Prog Biophys Mol Biol. 2019; 147:47–61.10.1016/j.pbiomolbio.2019.03.004. PubMed DOI PMC

Zhang  R, Shu  H, Wang  Y  et al. .  G-quadruplex structures are key modulators of somatic structural variants in cancers. Cancer Res. 2023; 83:1234–48.10.1158/0008-5472.CAN-22-3089. PubMed DOI PMC

Georgakopoulos-Soares  I, Morganella  S, Jain  N  et al. .  Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis. Genome Res. 2018; 28:1264–71.10.1101/gr.231688.117. PubMed DOI PMC

Chambers  VS, Marsico  G, Boutell  JM  et al. .  High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat Biotechnol. 2015; 33:877–81.10.1038/nbt.3295. PubMed DOI

Hui  WWI, Simeone  A, Zyner  KG  et al. .  Single-cell mapping of DNA G-quadruplex structures in human cancer cells. Sci Rep. 2021; 11:23641.10.1038/s41598-021-02943-3. PubMed DOI PMC

Lerner  LK, Sale  JE  Replication of G quadruplex DNA. Genes. 2019; 10:95.10.3390/genes10020095. PubMed DOI PMC

Sato  K, Knipscheer  P  G-quadruplex resolution: from molecular mechanisms to physiological relevance. DNA Repair. 2023; 130:103552.10.1016/j.dnarep.2023.103552. PubMed DOI

Lee  WTC, Yin  Y, Morten  MJ  et al. .  Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling. Nat Commun. 2021; 12:2525.10.1038/s41467-021-22830-9. PubMed DOI PMC

Sato  K, Martin-Pintado  N, Post  H  et al. .  Multistep mechanism of G-quadruplex resolution during DNA replication. Sci Adv. 2021; 7:eabf8653.10.1126/sciadv.abf8653. PubMed DOI PMC

Kruisselbrink  E, Guryev  V, Brouwer  K  et al. .  Mutagenic capacity of endogenous G4 DNA underlies genome instability in FANCJ-defective C. elegans. Curr Biol. 2008; 18:900–5.10.1016/j.cub.2008.05.013. PubMed DOI

Williams  SL, Casas-Delucchi  CS, Raguseo  F  et al. .  Replication-induced DNA secondary structures drive fork uncoupling and breakage. EMBO J. 2023; 42:e114334.10.15252/embj.2023114334. PubMed DOI PMC

Kumar  C, Batra  S, Griffith  JD  et al. .  The interplay of RNA:DNA hybrid structure and G-quadruplexes determines the outcome of R-loop-replisome collisions. eLife. 2021; 10:e72286.10.7554/eLife.72286. PubMed DOI PMC

Lopes  J, Piazza  A, Bermejo  R  et al. .  G-quadruplex-induced instability during leading strand replication. EMBO J. 2011; 30:4033–46.10.1038/emboj.2011.316. PubMed DOI PMC

Guilliam  TA, Yeeles  JTP  An updated perspective on the polymerase division of labor during eukaryotic DNA replication. Crit Rev Biochem Mol Biol. 2020; 55:469–81.10.1080/10409238.2020.1811630. PubMed DOI

Guilliam  TA, Yeeles  JT  The eukaryotic replisome tolerates leading-strand base damage by replicase switching. EMBO J. 2021; 40:e107037.10.15252/embj.2020107037. PubMed DOI PMC

Batra  S, Allwein  B, Kumar  C  et al. .  G-quadruplex-stalled eukaryotic replisome structure reveals helical inchworm DNA translocation. Science. 2025; 387:eadt1978.10.1126/science.adt1978. PubMed DOI

Stein  M, Eckert  KA  Impact of G-quadruplexes and chronic inflammation on genome instability: additive effects during carcinogenesis. Genes. 2021; 12:1779.10.3390/genes12111779. PubMed DOI PMC

Sahakyan  AB, Chambers  VS, Marsico  G  et al. .  Machine learning model for sequence-driven DNA G-quadruplex formation. Sci Rep. 2017; 7:14535.10.1038/s41598-017-14017-4. PubMed DOI PMC

Morganella  S, Alexandrov  LB, Glodzik  D  et al. .  The topography of mutational processes in breast cancer genomes. Nat Commun. 2016; 7:11383.10.1038/ncomms11383. PubMed DOI PMC

Frankish  A, Carbonell-Sala  S, Diekhans  M  et al. .  GENCODE: reference annotation for the human and mouse genomes in 2023. Nucleic Acids Res. 2023; 51:D942–9.10.1093/nar/gkac1071. PubMed DOI PMC

Georgakopoulos-Soares  I, Victorino  J, Parada  GE  et al. .  High-throughput characterization of the role of non-B DNA motifs on promoter function. Cell Genomics. 2022; 2:100111.10.1016/j.xgen.2022.100111. PubMed DOI PMC

Georgakopoulos-Soares  I, Mouratidis  I, Parada  GE  et al. .  Asymmetron: a toolkit for the identification of strand asymmetry patterns in biological sequences. Nucleic Acids Res. 2021; 49:e4.10.1093/nar/gkaa1052. PubMed DOI PMC

Kejnovská  I, Stadlbauer  P, Trantírek  L  et al. .  G-quadruplex formation by DNA sequences deficient in guanines: two tetrad parallel quadruplexes do not fold intramolecularly. 2021; 27:12115–25.10.1002/chem.202100895. PubMed DOI

Mergny  J-L, Li  J, Lacroix  L  et al. .  Thermal difference spectra: a specific signature for nucleic acid structures. Nucleic Acids Res. 2005; 33:e138.10.1093/nar/gni134. PubMed DOI PMC

Dahl  JM, Thomas  N, Tracy  MA  et al. .  Probing the mechanisms of two exonuclease domain mutators of DNA polymerase ε. Nucleic Acids Res. 2022; 50:962–74.10.1093/nar/gkab1255. PubMed DOI PMC

Fortune  JM, Stith  CM, Kissling  GE  et al. .  RPA and PCNA suppress formation of large deletion errors by yeast DNA polymerase δ. Nucleic Acids Res. 2006; 34:4335–41.10.1093/nar/gkl403. PubMed DOI PMC

Stith  CM, Sterling  J, Resnick  MA  et al. .  Flexibility of eukaryotic Okazaki fragment maturation through regulated strand displacement synthesis. J Biol Chem. 2008; 283:34129–40.10.1074/jbc.M806668200. PubMed DOI PMC

Nguyen  B, Sokoloski  J, Galletto  R  et al. .  Diffusion of human replication protein A along single-stranded DNA. J Mol Biol. 2014; 426:3246–61.10.1016/j.jmb.2014.07.014. PubMed DOI PMC

Li  M, Sengupta  B, Benkovic  SJ  et al. .  PCNA monoubiquitination is regulated by diffusion of Rad6/Rad18 complexes along RPA filaments. Biochemistry. 2020; 59:4694–702.10.1021/acs.biochem.0c00849. PubMed DOI PMC

Shah  SN, Opresko  PL, Meng  X  et al. .  DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D. Nucleic Acids Res. 2010; 38:1149–62.10.1093/nar/gkp1131. PubMed DOI PMC

Stein  M, Hile  SE, Weissensteiner  MH  et al. .  Variation in G-quadruplex sequence and topology differentially impacts human DNA polymerase fidelity. DNA Repair (Amst). 2022; 119:103402.10.1016/j.dnarep.2022.103402. PubMed DOI PMC

Hile  SE, Eckert  KA  Positive correlation between DNA polymerase alpha-primase pausing and mutagenesis within polypyrimidine/polypurine microsatellite sequences. J Mol Biol. 2004; 335:745–59.10.1016/j.jmb.2003.10.075. PubMed DOI

Das  M, Hile  SE, Brewster  J  et al. .  DNA polymerase zeta can efficiently replicate structures formed by AT/TA repeat sequences and prevent their deletion. Nucleic Acids Res. 2025; 53:gkae1254.10.1093/nar/gkae1254. PubMed DOI PMC

Shastri  N, Tsai  Y-C, Hile  S  et al. .  Genome-wide identification of structure-forming repeats as principal sites of fork collapse upon ATR inhibition. Mol Cell. 2018; 72:222–38.10.1016/j.molcel.2018.08.047. PubMed DOI PMC

Khare  V, Eckert  KA  The proofreading 3′→5′ exonuclease activity of DNA polymerases: a kinetic barrier to translesion DNA synthesis. Mutation Res. 2002; 510:45–54.10.1016/S0027-5107(02)00251-8. PubMed DOI

Zuker  M  Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 2003; 31:3406–15.10.1093/nar/gkg595. PubMed DOI PMC

Guiblet  WM, Cremona  MA, Cechova  M  et al. .  Long-read sequencing technology indicates genome-wide effects of non-B DNA on polymerization speed and error rate. Genome Res. 2018; 28:1767–78.10.1101/gr.241257.118. PubMed DOI PMC

DeJesus-Hernandez  M, Mackenzie  IR, Boeve  BF  et al. .  Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72:245–56.10.1016/j.neuron.2011.09.011. PubMed DOI PMC

Renton  AE, Majounie  E, Waite  A  et al. .  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72:257–68.10.1016/j.neuron.2011.09.010. PubMed DOI PMC

Rutherford  NJ, Heckman  MG, DeJesus-Hernandez  M  et al. .  Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging. 2012; 33:2950–7.10.1016/j.neurobiolaging.2012.07.005. PubMed DOI PMC

Prorok  P, Artufel  M, Aze  A  et al. .  Involvement of G-quadruplex regions in mammalian replication origin activity. Nat Commun. 2019; 10:3274.10.1038/s41467-019-11104-0. PubMed DOI PMC

Vouzas  AE, Gilbert  DM  Replication timing and transcriptional control: beyond cause and effect - part IV. Curr Opin Genet Dev. 2023; 79:102031.10.1016/j.gde.2023.102031. PubMed DOI PMC

Swan  MK, Johnson  RE, Prakash  L  et al. .  Structural basis of high-fidelity DNA synthesis by yeast DNA polymerase δ. Nat Struct Mol Biol. 2009; 16:979–86. PubMed PMC

Zheng  F, Georgescu  RE, Li  H  et al. .  Structure of eukaryotic DNA polymerase δ bound to the PCNA clamp while encircling DNA. Proc Natl Acad Sci USA. 2020; 117:30344–53.10.1073/pnas.2017637117. PubMed DOI PMC

Yuan  Z, Georgescu  R, Schauer  GD  et al. .  Structure of the polymerase ϵ holoenzyme and atomic model of the leading strand replisome. Nat Commun. 2020; 11:3156.10.1038/s41467-020-16910-5. PubMed DOI PMC

Haeusler  AR, Donnelly  CJ, Periz  G  et al. .  C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014; 507:195–200.10.1038/nature13124. PubMed DOI PMC

Šket  P, Pohleven  J, Kovanda  A  et al. .  Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiol Aging. 2015; 36:1091–6.10.1016/j.neurobiolaging.2014.09.012. PubMed DOI

Li  XM, Zheng  KW, Zhang  JY  et al. .  Guanine-vacancy-bearing G-quadruplexes responsive to guanine derivatives. Proc Natl Acad Sci USA. 2015; 112:14581–6.10.1073/pnas.1516925112. PubMed DOI PMC

Fleming  AM, Zhou  J, Wallace  SS  et al. .  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; 1:226–33.10.1021/acscentsci.5b00202. PubMed DOI PMC

Sun  D, Guo  K, Shin  Y-J  Evidence of the formation of G-quadruplex structures in the promoter region of the human vascular endothelial growth factor gene. Nucleic Acids Res. 2011; 39:1256–65.10.1093/nar/gkq926. PubMed DOI PMC

Sun  D, Liu  W-J, Guo  K  et al. .  The proximal promoter region of the human vascular endothelial growth factor gene has a G-quadruplex structure that can be targeted by G-quadruplex-interactive agents. Mol Cancer Ther. 2008; 7:880–9.10.1158/1535-7163.MCT-07-2119. PubMed DOI PMC

Kaiser  CE, Van Ert  NA, Agrawal  P  et al. .  Insight into the complexity of the i-motif and G-quadruplex DNA structures formed in the KRAS promoter and subsequent drug-induced gene repression. J Am Chem Soc. 2017; 139:8522–36.10.1021/jacs.7b02046. PubMed DOI PMC

del Mundo  IMA, Zewail-Foote  M, Kerwin  SM  et al. .  Alternative DNA structure formation in the mutagenic human c-MYC promoter. Nucleic Acids Res. 2017; 45:4929–43.10.1093/nar/gkx100. PubMed DOI PMC

Liu  L-Y, Ma  T-Z, Zeng  Y-L  et al. .  Structural basis of pyridostatin and its derivatives specifically binding to G-quadruplexes. J Am Chem Soc. 2022; 144:11878–87.10.1021/jacs.2c04775. PubMed DOI

Teng  F-Y, Jiang  Z-Z, Guo  M  et al. .  G-quadruplex DNA: a novel target for drug design. Cell Mol Life Sci. 2021; 78:6557–83.10.1007/s00018-021-03921-8. PubMed DOI PMC

Rodriguez  R, Miller  KM, Forment  JV  et al. .  Small-molecule–induced DNA damage identifies alternative DNA structures in human genes. Nat Chem Biol. 2012; 8:301–10.10.1038/nchembio.780. PubMed DOI PMC

Vesela  E, Chroma  K, Turi  Z  et al. .  Common chemical inductors of replication stress: focus on cell-based studies. Biomolecules. 2017; 7:19.10.3390/biom7010019. PubMed DOI PMC

Cheng  CH, Kuchta  RD  DNA polymerase epsilon: aphidicolin inhibition and the relationship between polymerase and exonuclease activity. Biochemistry. 1993; 32:8568–74.10.1021/bi00084a025. PubMed DOI

Aoyagi  N, Oshige  M, Hirose  F  et al. .  DNA polymerase ε from Drosophila melanogaster. Biochem Biophys Res Commun. 1997; 230:297–301.10.1006/bbrc.1996.5945. PubMed DOI

Baranovskiy  AG, Babayeva  ND, Suwa  Y  et al. .  Structural basis for inhibition of DNA replication by aphidicolin. Nucleic Acids Res. 2014; 42:14013–21.10.1093/nar/gku1209. PubMed DOI PMC

Esnault  C, Magat  T, Zine  El Aabidine A  et al. .  G4access identifies G-quadruplexes and their associations with open chromatin and imprinting control regions. Nat Genet. 2023; 55:1359–69.10.1038/s41588-023-01437-4. PubMed DOI

Jana  J, Weisz  K  Thermodynamic stability of G-quadruplexes: impact of sequence and environment. ChemBioChem. 2021; 22:2848–56.10.1002/cbic.202100127. PubMed DOI PMC

Castillo  Bosch P, Segura-Bayona  S, Koole  W  et al. .  FANCJ promotes DNA synthesis through G-quadruplex structures. EMBO J. 2014; 33:2521–33.10.15252/embj.201488663. PubMed DOI PMC

Hogg  M, Osterman  P, Bylund  GO  et al. .  Structural basis for processive DNA synthesis by yeast DNA polymerase varepsilon. Nat Struct Mol Biol. 2014; 21:49–55.10.1038/nsmb.2712. PubMed DOI

Jain  R, Rice  WJ, Malik  R  et al. .  Cryo-EM structure and dynamics of eukaryotic DNA polymerase delta holoenzyme. Nat Struct Mol Biol. 2019; 26:955–62.10.1038/s41594-019-0305-z. PubMed DOI PMC

Lancey  C, Tehseen  M, Raducanu  VS  et al. .  Structure of the processive human Pol delta holoenzyme. Nat Commun. 2020; 11:1109.10.1038/s41467-020-14898-6. PubMed DOI PMC

Roske  JJ, Yeeles  JTP  Structural basis for processive daughter-strand synthesis and proofreading by the human leading-strand DNA polymerase Pol epsilon. Nat Struct Mol Biol. 2024; 31:1921–31.10.1038/s41594-024-01370-y. PubMed DOI PMC

Nair  DT, Johnson  RE, Prakash  L  et al. .  Rev1 employs a novel mechanism of DNA synthesis using a protein template. Science. 2005; 309:2219–22.10.1126/science.1116336. PubMed DOI

Zahn  KE, Wallace  SS, Doublie  S  DNA polymerases provide a canon of strategies for translesion synthesis past oxidatively generated lesions. Curr Opin Struct Biol. 2011; 21:358–69.10.1016/j.sbi.2011.03.008. PubMed DOI PMC

Kumar  N, Sahoo  B, Varun  KA  et al. .  Effect of loop length variation on quadruplex-Watson Crick duplex competition. Nucleic Acids Res. 2008; 36:4433–42.10.1093/nar/gkn402. PubMed DOI PMC

Chalikian  TV, Liu  L, Macgregor  RB  Duplex-tetraplex equilibria in guanine- and cytosine-rich DNA. Biophys Chem. 2020; 267:106473.10.1016/j.bpc.2020.106473. PubMed DOI

Piazza  A, Adrian  M, Samazan  F  et al. .  Short loop length and high thermal stability determine genomic instability induced by G-quadruplex-forming minisatellites. EMBO J. 2015; 34:1718–34.10.15252/embj.201490702. PubMed DOI PMC

Mathad  RI, Hatzakis  E, Dai  J  et al. .  c-MYC promoter G-quadruplex formed at the 5′-end of NHE III1 element: insights into biological relevance and parallel-stranded G-quadruplex stability. Nucleic Acids Res. 2011; 39:9023–33.10.1093/nar/gkr612. PubMed DOI PMC

Schiavone  D, Jozwiakowski  S, Romanello  M  et al. .  PrimPol is required for replicative tolerance of G-quadruplexes in vertebrate cells. Mol Cell. 2016; 61:161–9.10.1016/j.molcel.2015.10.038. PubMed DOI PMC

Thys  RG, Wang  YH  DNA replication dynamics of the GGGGCC repeat of the C9orf72 gene. J Biol Chem. 2015; 290:28953–62.10.1074/jbc.M115.660324. PubMed DOI PMC

Zhou  B, Liu  C, Geng  Y  et al. .  Topology of a G-quadruplex DNA formed by C9orf72 hexanucleotide repeats associated with ALS and FTD. Sci Rep. 2015; 5:16673.10.1038/srep16673. PubMed DOI PMC

Su  Z, Zhang  Y, Gendron  TF  et al. .  Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron. 2014; 83:1043–50.10.1016/j.neuron.2014.07.041. PubMed DOI PMC

Li  S, Shen  X  Long interspersed nuclear element 1 and B1/alu repeats blueprint genome compartmentalization. Curr Opin Genet Dev. 2023; 80:102049. PubMed

Howell  R, Usdin  K  The ability to form intrastrand tetraplexes is an evolutionarily conserved feature of the 3′ end of L1 retrotransposons. Mol Biol Evol. 1997; 14:144–55.10.1093/oxfordjournals.molbev.a025747. PubMed DOI

Kejnovsky  E, Tokan  V, Lexa  M  Transposable elements and G-quadruplexes. Chromosome Res. 2015; 23:615–23.10.1007/s10577-015-9491-7. PubMed DOI

Ardeljan  D, Steranka  JP, Liu  C  et al. .  Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication. Nat Struct Mol Biol. 2020; 27:168–78. PubMed PMC

Salas  TR, Petruseva  I, Lavrik  O  et al. .  Human replication protein A unfolds telomeric G-quadruplexes. Nucleic Acids Res. 2006; 34:4857–65.10.1093/nar/gkl564. PubMed DOI PMC

Ray  S, Qureshi  MH, Malcolm  DW  et al. .  RPA-mediated unfolding of systematically varying G-quadruplex structures. Biophys J. 2013; 104:2235–45.10.1016/j.bpj.2013.04.004. PubMed DOI PMC

Wang  Y-R, Guo  T-T, Zheng  Y-T  et al. .  Replication protein A plays multifaceted roles complementary to specialized helicases in processing G-quadruplex DNA. iScience. 2021; 24:102493.10.1016/j.isci.2021.102493. PubMed DOI PMC

Sparks  MA, Singh  SP, Burgers  PM  et al. .  Complementary roles of Pif1 helicase and single stranded DNA binding proteins in stimulating DNA replication through G-quadruplexes. Nucleic Acids Res. 2019; 47:8595–605. PubMed PMC

Pytko  KG, Dannenberg  RL, Eckert  KA  et al. .  Replication of [AT/TA](25) microsatellite sequences by Human DNA polymerase delta holoenzymes is dependent on dNTP and RPA levels. Biochemistry. 2024; 63:969–83.10.1021/acs.biochem.4c00006. PubMed DOI

Lormand  JD, Buncher  N, Murphy  CT  et al. .  DNA polymerase δ stalls on telomeric lagging strand templates independently from G-quadruplex formation. Nucleic Acids Res. 2013; 41:10323–33.10.1093/nar/gkt813. PubMed DOI PMC

Jones  ML, Baris  Y, Taylor  MRG  et al. .  Structure of a human replisome shows the organisation and interactions of a DNA replication machine. EMBO J. 2021; 40:e108819.10.15252/embj.2021108819. PubMed DOI PMC

Lerner  LK, Holzer  S, Kilkenny  ML  et al. .  Timeless couples G-quadruplex detection with processing by DDX11 helicase during DNA replication. EMBO J. 2020; 39:e104185.10.15252/embj.2019104185. PubMed DOI PMC

Biffi  G, Tannahill  D, Miller  J  et al. .  Elevated levels of G-quadruplex formation in human stomach and liver cancer tissues. PLoS One. 2014; 9:e102711.10.1371/journal.pone.0102711. PubMed DOI PMC

Zimmer  J, Tacconi  EMC, Folio  C  et al. .  Targeting BRCA1 and BRCA2 deficiencies with G-quadruplex-interacting compounds. Mol Cell. 2016; 61:449–60.10.1016/j.molcel.2015.12.004. PubMed DOI PMC

Groelly  FJ, Porru  M, Zimmer  J  et al. .  Anti-tumoural activity of the G-quadruplex ligand pyridostatin against BRCA1/2-deficient tumours. EMBO Mol Med. 2022; 14:e14501.10.15252/emmm.202114501. PubMed DOI PMC

Bossaert  M, Pipier  A, Riou  JF  et al. .  Transcription-associated topoisomerase 2alpha (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands. eLife. 2021; 10:e65184.10.7554/eLife.65184. PubMed DOI PMC

Olivieri  M, Cho  T, Alvarez-Quilon  A  et al. .  A genetic map of the response to DNA damage in Human cells. Cell. 2020; 182:481–496.10.1016/j.cell.2020.05.040. PubMed DOI PMC

Xu  H, Di  Antonio M, McKinney  S  et al. .  CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017; 8:14432.10.1038/ncomms14432. PubMed DOI PMC

Koh  GCC, Boushaki  S, Zhao  SJ  et al. .  The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells. Nat Genet. 2024; 56:23–6.10.1038/s41588-023-01602-9. PubMed DOI PMC