Recent experiments provide fascinating examples of how G4 DNA and G4 RNA structures—aka quadruplexes—may contribute to normal biology and to genomic pathologies. Quadruplexes are transient and therefore difficult to identify directly in living cells, which initially caused skepticism regarding not only their biological relevance but even their existence. There is now compelling evidence for functions of some G4 motifs and the corresponding quadruplexes in essential processes, including initiation of DNA replication, telomere maintenance, regulated recombination in immune evasion and the immune response, control of gene expression, and genetic and epigenetic instability. Recognition and resolution of quadruplex structures is therefore an essential component of genome biology. We propose that G4 motifs and structures that participate in key processes compose the G4 genome, analogous to the transcriptome, proteome, or metabolome. This is a new view of the genome, which sees DNA as not only a simple alphabet but also a more complex geography. The challenge for the future is to systematically identify the G4 motifs that form quadruplexes in living cells and the features that confer on specific G4 motifs the ability to function as structural elements.
Vyšlo v časopise: The G4 Genome. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003468 Kategorie: Review prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003468
1. GellertM, LipsettMN, DaviesDR (1962) Helix formation by guanylic acid. Proc Natl Acad Sci U S A 48 : 2014–2018.
2. SenD, GilbertW (1988) Formation of parallel four-stranded complexes by guanine rich motifs in DNA and its implications for meiosis. Nature 334 : 364–366.
3. KimJ, CheongC, MoorePB (1991) Tetramerization of an RNA oligonucleotide containing a GGGG sequence. Nature 351 : 331–332.
4. PhanAT, KuryavyiV, PatelDJ (2006) DNA architecture: from G to Z. Curr Opin Struct Biol 16 : 288–298.
5. PatelDJ, PhanAT, KuryavyiV (2007) Human telomere, oncogenic promoter and 5′-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics. Nucleic Acids Res 35 : 7429–7455.
6. BesnardE, BabledA, LapassetL, MilhavetO, ParrinelloH, et al. (2012) Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat Struct Mol Biol 19 : 837–844.
7. TuesuwanB, KernJT, ThomasPW, RodriguezM, LiJ, et al. (2008) Simian virus 40 large T-antigen G-quadruplex DNA helicase inhibition by G-quadruplex DNA-interactive agents. Biochemistry 47 : 1896–1909.
8. NorseenJ, JohnsonFB, LiebermanPM (2009) Role for G-quadruplex RNA binding by Epstein-Barr virus nuclear antigen 1 in DNA replication and metaphase chromosome attachment. J Virol 83 : 10336–10346.
9. ParkinsonGN, LeeMP, NeidleS (2002) Crystal structure of parallel quadruplexes from human telomeric DNA. Nature 417 : 876–880.
10. YuHQ, MiyoshiD, SugimotoN (2006) Characterization of structure and stability of long telomeric DNA G-quadruplexes. J Am Chem Soc 128 : 15461–15468.
11. HaiderSM, NeidleS, ParkinsonGN (2011) A structural analysis of G-quadruplex/ligand interactions. Biochimie 93 : 1239–1251.
12. LukeB, LingnerJ (2009) TERRA: telomeric repeat-containing RNA. EMBO J 28 : 2503–2510.
13. MartadinataH, HeddiB, LimKW, PhanAT (2011) Structure of long human telomeric RNA (TERRA): G-quadruplexes formed by four and eight UUAGGG repeats are stable building blocks. Biochemistry 50 : 6455–6461.
14. XuY, SuzukiY, ItoK, KomiyamaM (2010) Telomeric repeat-containing RNA structure in living cells. Proc Natl Acad Sci U S A 107 : 14579–14584.
15. DengZ, NorseenJ, WiedmerA, RiethmanH, LiebermanPM (2009) TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell 35 : 403–413.
16. BiffiG, TannahillD, BalasubramanianS (2012) An intramolecular G-quadruplex structure is required for binding of telomeric repeat-containing RNA to the telomeric protein TRF2. J Am Chem Soc 134 : 11974–11976.
17. de LangeT (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19 : 2100–2110.
18. SfeirA, KosiyatrakulST, HockemeyerD, MacRaeSL, KarlsederJ, et al. (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138 : 90–103.
19. SfeirA, de LangeT (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336 : 593–597.
20. SmithJS, ChenQ, YatsunykLA, NicoludisJM, GarciaMS, et al. (2011) Rudimentary G-quadruplex-based telomere capping in Saccharomyces cerevisiae. Nat Struct Mol Biol 18 : 478–485.
21. SunH, KarowJK, HicksonID, MaizelsN (1998) The Bloom's syndrome helicase unwinds G4 DNA. J Biol Chem 273 : 27587–27592.
22. FryM, LoebLA (1999) Human Werner syndrome DNA helicase unwinds tetrahelical structures of the fragile X syndrome repeat sequence d(CGG)n. J Biol Chem 274 : 12797–12802.
23. LondonTB, BarberLJ, MosedaleG, KellyGP, BalasubramanianS, et al. (2008) FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts. J Biol Chem 283 : 36132–36139.
24. WuY, Shin-YaK, BroshRMJr (2008) FANCJ helicase defective in Fanconi anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability. Mol Cell Biol 28 : 4116–4128.
25. WuY, SommersJA, KhanI, de WinterJP, BroshRMJr (2012) Biochemical characterization of Warsaw breakage syndrome helicase. J Biol Chem 287 : 1007–1021.
26. SandersCM (2010) Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity. Biochem J 430 : 119–128.
27. DingH, SchertzerM, WuX, GertsensteinM, SeligS, et al. (2004) Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117 : 873–886.
28. CrabbeL, VerdunRE, HaggblomCI, KarlsederJ (2004) Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306 : 1951–1953.
29. BarefieldC, KarlsederJ (2012) The BLM helicase contributes to telomere maintenance through processing of late-replicating intermediate structures. Nucleic Acids Res 40 : 7358–7367.
30. UringaEJ, YoudsJL, LisaingoK, LansdorpPM, BoultonSJ (2011) RTEL1: an essential helicase for telomere maintenance and the regulation of homologous recombination. Nucleic Acids Res 39 : 1647–1655.
31. VannierJB, Pavicic-KaltenbrunnerV, PetalcorinMI, DingH, BoultonSJ (2012) RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149 : 795–806.
32. KruisselbrinkE, GuryevV, BrouwerK, PontierDB, CuppenE, et al. (2008) Mutagenic capacity of endogenous G4 DNA underlies genome instability in FANCJ-defective C. elegans. Curr Biol 18 : 900–905.
33. PiazzaA, BouleJB, LopesJ, MingoK, LargyE, et al. (2010) Genetic instability triggered by G-quadruplex interacting Phen-DC compounds in Saccharomyces cerevisiae. Nucleic Acids Res 38 : 4337–4348.
34. LopesJ, PiazzaA, BermejoR, KriegsmanB, ColosioA, et al. (2011) G-quadruplex-induced instability during leading-strand replication. EMBO J 30 : 4033–4046.
35. PaeschkeK, CapraJA, ZakianVA (2011) DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase. Cell 145 : 678–691.
36. DavisL, MaizelsN (2011) G4 DNA: at risk in the genome. EMBO J 30 : 3878–3879.
37. CahoonLA, SeifertHS (2009) An alternative DNA structure is necessary for pilin antigenic variation in Neisseria gonorrhoeae. Science 325 : 764–767.
38. CahoonLA, SeifertHS (2013) Transcription of a cis-acting, noncoding, small RNA is required for pilin antigenic variation in Neisseria gonorrhoeae. PLoS Pathog 9: e1003074 doi:10.1371/journal.ppat.1003074.
39. KuryavyiV, CahoonLA, SeifertHS, PatelDJ (2012) RecA-binding pilE G4 sequence essential for pilin antigenic variation forms monomeric and 5′ end-stacked dimeric parallel G-quadruplexes. Structure 20 : 2090–2102.
40. DuquetteML, HandaP, VincentJA, TaylorAF, MaizelsN (2004) Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA. Genes Dev 18 : 1618–1629.
41. DuquetteML, PhamP, GoodmanMF, MaizelsN (2005) AID binds to transcription-induced structures in c-MYC that map to regions associated with translocation and hypermutation. Oncogene 24 : 5791–5798.
42. DuquetteML, HuberMD, MaizelsN (2007) G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas. Cancer Res 67 : 2586–2594.
43. MaizelsN (2006) Dynamic roles for G4 DNA in the biology of eukaryotic cells. Nat Struct Mol Biol 13 : 1055–1059.
44. LarsonED, DuquetteML, CummingsWJ, StreiffRJ, MaizelsN (2005) MutSalpha binds to and promotes synapsis of transcriptionally activated immunoglobulin switch regions. Curr Biol 15 : 470–474.
45. EhratEA, JohnsonBR, WilliamsJD, BorchertGM, LarsonED (2012) G-quadruplex recognition activities of E. Coli MutS. BMC Mol Biol 13 : 23.
46. EddyJ, MaizelsN (2006) Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res 34 : 3887–3896.
47. HuppertJL, BalasubramanianS (2007) G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res 35 : 406–413.
48. EddyJ, MaizelsN (2009) Selection for the G4 DNA motif at the 5′ end of human genes. Mol Carcinog 48 : 319–325.
49. DuZ, ZhaoY, LiN (2009) Genome-wide colonization of gene regulatory elements by G4 DNA motifs. Nucleic Acids Res 37 : 6784–6798.
50. EddyJ, VallurAC, VarmaS, LiuH, ReinholdWC, et al. (2011) G4 motifs correlate with promoter-proximal transcriptional pausing in human genes. Nucleic Acids Res 39 : 4975–4983.
51. BalasubramanianS, HurleyLH, NeidleS (2011) Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 10 : 261–275.
52. RaiberEA, KranasterR, LamE, NikanM, BalasubramanianS (2012) A non-canonical DNA structure is a binding motif for the transcription factor SP1 in vitro. Nucleic Acids Res 40 : 1499–1508.
53. BugautA, BalasubramanianS (2012) 5′-UTR RNA G-quadruplexes: translation regulation and targeting. Nucleic Acids Res 40 : 4727–4741.
54. EddyJ, MaizelsN (2008) Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes. Nucleic Acids Res 36 : 1321–1333.
55. KuryavyiV, PatelDJ (2010) Solution structure of a unique G-quadruplex scaffold adopted by a guanosine-rich human intronic sequence. Structure 18 : 73–82.
56. DecorsiereA, CayrelA, VagnerS, MillevoiS (2011) Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage. Genes Dev 25 : 220–225.
57. Skourti-StathakiK, ProudfootNJ, GromakN (2011) Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42 : 794–805.
58. AguileraA, Garcia-MuseT (2012) R loops: from transcription byproducts to threats to genome stability. Mol Cell 46 : 115–124.
59. KimN, Jinks-RobertsonS (2012) Transcription as a source of genome instability. Nat Rev Genet 13 : 204–214.
60. GinnoPA, LottPL, ChristensenHC, KorfI, ChedinF (2012) R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol Cell 45 : 814–825.
61. RodriguezR, MillerKM, FormentJV, BradshawCR, NikanM, et al. (2012) Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat Chem Biol 8 : 301–310.
62. SantoroMR, BraySM, WarrenST (2012) Molecular mechanisms of Fragile X syndrome: a twenty-year perspective. Annu Rev Pathol 7 : 219–245.
63. DeJesus-HernandezM, MackenzieIR, BoeveBF, BoxerAL, BakerM, et al. (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72 : 245–256.
64. FrattaP, MizielinskaS, NicollAJ, ZlohM, FisherEM, et al. (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2 : 1016.
65. RentonAE, MajounieE, WaiteA, Simon-SanchezJ, RollinsonS, et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72 : 257–268.
66. KobayashiH, AbeK, MatsuuraT, IkedaY, HitomiT, et al. (2011) Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am J Hum Genet 89 : 121–130.
67. BorelC, MigliavaccaE, LetourneauA, GagnebinM, BenaF, et al. (2012) Tandem repeat sequence variation as causative cis-eQTLs for protein-coding gene expression variation: the case of CSTB. Hum Mutat 33 : 1302–1309.
68. MeadS, WebbTE, CampbellTA, BeckJ, LinehanJM, et al. (2007) Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129. Neurology 69 : 730–738.
69. LehmannS, HarrisDA (1996) Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform. Proc Natl Acad Sci U S A 93 : 5610–5614.
70. SarkiesP, ReamsC, SimpsonLJ, SaleJE (2010) Epigenetic instability due to defective replication of structured DNA. Mol Cell 40 : 703–713.
71. SarkiesP, MuratP, PhillipsLG, PatelKJ, BalasubramanianS, et al. (2011) FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA. Nucleic Acids Res 40 : 1485–1498.
72. SarkiesP, SaleJE (2011) Propagation of histone marks and epigenetic memory during normal and interrupted DNA replication. Cell Mol Life Sci 69 : 697–716.
73. GoldbergAD, BanaszynskiLA, NohKM, LewisPW, ElsaesserSJ, et al. (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140 : 678–691.
74. WongLH, McGhieJD, SimM, AndersonMA, AhnS, et al. (2010) ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells. Genome Res 20 : 351–360.
75. LawMJ, LowerKM, VoonHP, HughesJR, GarrickD, et al. (2010) ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell 143 : 367–378.
76. MirkinSM (2007) Expandable DNA repeats and human disease. Nature 447 : 932–940.
77. WongHM, HuppertJL (2009) Stable G-quadruplexes are found outside nucleosome-bound regions. Mol Biosyst 5 : 1713–1719.
78. HalderK, HalderR, ChowdhuryS (2009) Genome-wide analysis predicts DNA structural motifs as nucleosome exclusion signals. Mol Biosyst 5 : 1703–1712.
79. HalderR, HalderK, SharmaP, GargG, SenguptaS, et al. (2010) Guanine quadruplex DNA structure restricts methylation of CpG dinucleotides genome-wide. Mol Biosyst 6 : 2439–2447.
80. DeS, MichorF (2011) DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat Struct Mol Biol 18 : 950–955.
81. BiffiG, TannahillD, McCafferty, SubramanianS (2013) Quantitative visualization of DNA G-quadruplex structures in human cells. Nature Chem 5 : 182–186.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
