G-quadruplex as an essential structural element in cytomegalovirus replication origin.
G-Quadruplexes
Cytomegalovirus
/ genetics
Humans
Virus Replication
/ genetics
Replication Origin
/ genetics
DNA Replication
Viral Proteins
/ metabolism
Immediate-Early Proteins
/ metabolism
DNA, Viral
/ genetics
Trans-Activators
/ metabolism
DNA-Binding Proteins
/ metabolism
Herpesvirus 4, Human
/ genetics
Protein Binding
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 Aug 2024
27 Aug 2024
Historique:
received:
22
02
2024
accepted:
16
08
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
epublish
Résumé
G-quadruplex (G4) structures are found in eukaryotic cell replication origins, but their role in origin function remains unclear. In this study G4 motifs are found in the lytic DNA replication origin (oriLyt) of human cytomegalovirus (HCMV) and recombinant viruses show that a G4 motif in oriLyt essential region I (ER-I) is necessary for viral growth. Replication assays of oriLyt-containing plasmids and biochemical/biophysical analyses show that G4 formation in ER-I is crucial for viral DNA replication. G4 pull-down analysis identifies viral DNA replication factors, such as IE2, UL84, and UL44, as G4-binding proteins. In enzyme-linked immunosorbent assays, specific G4-binding ligands inhibit G4 binding by the viral proteins. The Epstein-Barr virus oriLyt core element also forms a stable G4 that could substitute for the oriLyt ER-I G4 in HCMV. These results demonstrate that viral G4s in replication origins represent an essential structural element in recruiting replication factors and might be a therapeutic target against viral infections.
Identifiants
pubmed: 39191758
doi: 10.1038/s41467-024-51797-6
pii: 10.1038/s41467-024-51797-6
doi:
Substances chimiques
Viral Proteins
0
Immediate-Early Proteins
0
DNA, Viral
0
IE2 protein, Cytomegalovirus
0
UL84 protein, Cytomegalovirus
145186-23-8
Trans-Activators
0
ICP36 protein, Cytomegalovirus
0
DNA-Binding Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7353Subventions
Organisme : National Research Foundation of Korea (NRF)
ID : 2020R1A4A1018019
Organisme : National Research Foundation of Korea (NRF)
ID : 2021M3A9I2080488
Organisme : National Research Foundation of Korea (NRF)
ID : 2022R1A2C1006748
Informations de copyright
© 2024. The Author(s).
Références
Varshney, D., Spiegel, J., Zyner, K., Tannahill, D. & Balasubramanian, S. The regulation and functions of DNA and RNA G-quadruplexes. Nat. Rev. Mol. Cell Biol. 21, 459–474 (2020).
pubmed: 32313204
pmcid: 7115845
doi: 10.1038/s41580-020-0236-x
Rhodes, D. & Lipps, H. J. G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res. 43, 8627–8637 (2015).
pubmed: 26350216
pmcid: 4605312
doi: 10.1093/nar/gkv862
Hansel-Hertsch, R., Antonio, M. D. & Balasubramanian, S. DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat. Rev. Mol. Cell Biol. 18, 279–284 (2017).
pubmed: 28225080
doi: 10.1038/nrm.2017.3
Valton, A. L. & Prioleau, M. N. G-Quadruplexes in DNA replication: a problem or a necessity? Trends Genet. 32, 697–706 (2016).
doi: 10.1016/j.tig.2016.09.004
Bryan, T. M. Mechanisms of DNA replication and repair: insights from the study of G-Quadruplexes. Molecules 24, 3439 (2019).
pubmed: 31546714
pmcid: 6804030
doi: 10.3390/molecules24193439
Cayrou, C. et al. New insights into replication origin characteristics in metazoans. Cell Cycle 11, 658–667 (2012).
pubmed: 22373526
pmcid: 3318102
doi: 10.4161/cc.11.4.19097
Besnard, E. et al. Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat. Struct. Mol. Biol. 19, 837–844 (2012).
pubmed: 22751019
doi: 10.1038/nsmb.2339
Cayrou, C. et al. The chromatin environment shapes DNA replication origin organization and defines origin classes. Genome Res. 25, 1873–1885 (2015).
pubmed: 26560631
pmcid: 4665008
doi: 10.1101/gr.192799.115
Langley, A. R., Gräf, S., Smith, J. C. & Krude, T. Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq). Nucleic Acids Res. 44, 10230–10247 (2016).
pubmed: 27587586
pmcid: 5137433
Valton, A. L. et al. G4 motifs affect origin positioning and efficiency in two vertebrate replicators. EMBO J. 33, 732–746 (2014).
pubmed: 24521668
pmcid: 4000090
doi: 10.1002/embj.201387506
Prorok, P. et al. Involvement of G-quadruplex regions in mammalian replication origin activity. Nat. Commun. 10, 3274 (2019).
pubmed: 31332171
pmcid: 6646384
doi: 10.1038/s41467-019-11104-0
Mocarski, E. S., Shenk, T., Griffiths, P. D. & Pass, R. F. Cytomegaloviruses. In Fields virology (eds. D. M. Knipe, P. M. Howley, J. I. Cohen, D. E. Griffin, R. A. Lamb, M. A. Martin, V. R. Racaniello, & B. Roizman) (Lippincott Williams & Wilkins, Philadelphia, PA, 2013).
Anders, D. G. & Punturieri, S. M. Multicomponent origin of cytomegalovirus lytic-phase DNA replication. J. Virol. 65, 931–937 (1991).
pubmed: 1846206
pmcid: 239834
doi: 10.1128/jvi.65.2.931-937.1991
Pari, G. S. & Anders, D. G. Eleven loci encoding trans-acting factors are required for transient complementation of human cytomegalovirus oriLyt-dependent DNA replication. J. Virol. 67, 6979–6988 (1993).
pubmed: 8230421
pmcid: 238157
doi: 10.1128/jvi.67.12.6979-6988.1993
Chee, M. S. et al. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr. Top. Microbiol. Immunol. 154, 125–169 (1990).
pubmed: 2161319
Davison, A. J. et al. The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J. Gen. Virol. 84, 17–28 (2003).
pubmed: 12533697
doi: 10.1099/vir.0.18606-0
Pari, G. S., Kacica, M. A. & Anders, D. G. Open reading frames UL44, IRS1/TRS1, and UL36-38 are required for transient complementation of human cytomegalovirus oriLyt-dependent DNA synthesis. J. Virol. 67, 2575–2582 (1993).
pubmed: 8386266
pmcid: 237578
doi: 10.1128/jvi.67.5.2575-2582.1993
Smith, J. A. & Pari, G. S. Expression of human cytomegalovirus UL36 and UL37 genes is required for viral DNA replication. J. Virol. 69, 1925–1931 (1995).
pubmed: 7853536
pmcid: 188810
doi: 10.1128/jvi.69.3.1925-1931.1995
Pari, G. S. Nuts and bolts of human cytomegalovirus lytic DNA replication. Curr. Top. Microbiol. Immunol. 325, 153–166 (2008).
pubmed: 18637505
Xu, Y., Cei, S. A., Rodriguez Huete, A., Colletti, K. S. & Pari, G. S. Human cytomegalovirus DNA replication requires transcriptional activation via an IE2- and UL84-responsive bidirectional promoter element within oriLyt. J. Virol. 78, 11664–11677 (2004).
pubmed: 15479808
pmcid: 523242
doi: 10.1128/JVI.78.21.11664-11677.2004
Sarisky, R. T. & Hayward, G. S. Evidence that the UL84 gene product of human cytomegalovirus is essential for promoting oriLyt-dependent DNA replication and formation of replication compartments in cotransfection assays. J. Virol. 70, 7398–7413 (1996).
pubmed: 8892858
pmcid: 190807
doi: 10.1128/jvi.70.11.7398-7413.1996
Zhu, Y., Huang, L. & Anders, D. G. Human cytomegalovirus oriLyt sequence requirements. J. Virol. 72, 4989–4996 (1998).
pubmed: 9573268
pmcid: 110061
doi: 10.1128/JVI.72.6.4989-4996.1998
Colletti, K. S., Smallenburg, K. E., Xu, Y. & Pari, G. S. Human cytomegalovirus UL84 interacts with an RNA stem-loop sequence found within the RNA/DNA hybrid region of oriLyt. J. Virol. 81, 7077–7085 (2007).
pubmed: 17459920
pmcid: 1933308
doi: 10.1128/JVI.00058-07
Kagele, D., Gao, Y., Smallenburg, K. & Pari, G. S. Interaction of HCMV UL84 with C/EBPalpha transcription factor binding sites within oriLyt is essential for lytic DNA replication. Virology 392, 16–23 (2009).
pubmed: 19631360
doi: 10.1016/j.virol.2009.06.035
Kagele, D., Rossetto, C. C., Tarrant, M. T. & Pari, G. S. Analysis of the interactions of viral and cellular factors with human cytomegalovirus lytic origin of replication, oriLyt. Virology 424, 106–114 (2012).
pubmed: 22236369
doi: 10.1016/j.virol.2011.12.010
Huang, L., Zhu, Y. & Anders, D. G. The variable 3’ ends of a human cytomegalovirus oriLyt transcript (SRT) overlap an essential, conserved replicator element. J. Virol. 70, 5272–5281 (1996).
pubmed: 8764037
pmcid: 190484
doi: 10.1128/jvi.70.8.5272-5281.1996
Spector, D. J. UL84-independent replication of human cytomegalovirus strains conferred by a single codon change in UL122. Virology 476, 345–354 (2015).
pubmed: 25577152
doi: 10.1016/j.virol.2014.12.031
Manska, S. & Rossetto, C. C. Characteristics of Immediate-Early 2 (IE2) and UL84 Proteins in UL84-Independent Strains of Human Cytomegalovirus (HCMV). Microbiol. Spectr. 9, e0053921 (2021).
pubmed: 34550009
doi: 10.1128/Spectrum.00539-21
Ravichandran, S. et al. Genome-wide analysis of regulatory G-quadruplexes affecting gene expression in human cytomegalovirus. PLoS Pathog. 14, e1007334 (2018).
pubmed: 30265731
pmcid: 6179306
doi: 10.1371/journal.ppat.1007334
Chambers, V. S. et al. High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat. Biotechnol. 33, 877–881 (2015).
pubmed: 26192317
doi: 10.1038/nbt.3295
Ravichandran, S., Razzaq, M., Parveen, N., Ghosh, A. & Kim, K. K. The effect of hairpin loop on the structure and gene expression activity of the long-loop G-quadruplex. Nucleic Acids Res. 49, 10689–10706 (2021).
pubmed: 34450640
pmcid: 8501965
doi: 10.1093/nar/gkab739
Burge, S., Parkinson, G. N., Hazel, P., Todd, A. K. & Neidle, S. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 34, 5402–5415 (2006).
pubmed: 17012276
pmcid: 1636468
doi: 10.1093/nar/gkl655
Bochman, M. L., Paeschke, K. & Zakian, V. A. DNA secondary structures: stability and function of G-quadruplex structures. Nat. Rev. Genet 13, 770–780 (2012).
pubmed: 23032257
pmcid: 3725559
doi: 10.1038/nrg3296
Davis, J. T. G-quartets 40 years later: from 5’-GMP to molecular biology and supramolecular chemistry. Angew. Chem. Int. Ed. Engl. 43, 668–698 (2004).
pubmed: 14755695
doi: 10.1002/anie.200300589
Ren, J. & Chaires, J. B. Sequence and structural selectivity of nucleic acid binding ligands. Biochemistry 38, 16067–16075 (1999).
pubmed: 10587429
doi: 10.1021/bi992070s
Georgakopoulos-Soares, I. et al. Alternative splicing modulation by G-quadruplexes. Nat. Commun. 13, 2404 (2022).
pubmed: 35504902
pmcid: 9065059
doi: 10.1038/s41467-022-30071-7
Mergny, J. L., Li, J., Lacroix, L., Amrane, S. & Chaires, J. B. Thermal difference spectra: a specific signature for nucleic acid structures. Nucleic Acids Res. 33, e138 (2005).
pubmed: 16157860
pmcid: 1201377
doi: 10.1093/nar/gni134
Zheng, K. W., Chen, Z., Hao, Y. H. & Tan, Z. Molecular crowding creates an essential environment for the formation of stable G-quadruplexes in long double-stranded DNA. Nucleic Acids Res. 38, 327–338 (2010).
pubmed: 19858105
doi: 10.1093/nar/gkp898
Nakano, S., Miyoshi, D. & Sugimoto, N. Effects of molecular crowding on the structures, interactions, and functions of nucleic acids. Chem. Rev. 114, 2733–2758 (2014).
pubmed: 24364729
doi: 10.1021/cr400113m
Dabral, P., Babu, J., Zareie, A. & Verma, S. C. LANA and hnRNP A1 regulate the translation of LANA mRNA through G-Quadruplexes. J. Virol. 94, e01508–e01519 (2020).
pubmed: 31723020
pmcid: 7000962
doi: 10.1128/JVI.01508-19
Day, H. A., Pavlou, P. & Waller, Z. A. i-Motif DNA: structure, stability and targeting with ligands. Bioorg. Med. Chem. 22, 4407–4418 (2014).
pubmed: 24957878
doi: 10.1016/j.bmc.2014.05.047
Abou Assi, H., Garavís, M., González, C. & Damha, M. J. i-Motif DNA: structural features and significance to cell biology. Nucleic Acids Res. 46, 8038–8056 (2018).
pubmed: 30124962
pmcid: 6144788
doi: 10.1093/nar/gky735
Zeraati, M. et al. I-motif DNA structures are formed in the nuclei of human cells. Nat. Chem. 10, 631–637 (2018).
pubmed: 29686376
doi: 10.1038/s41557-018-0046-3
Pizzorno, M. C., O’Hare, P., Sha, L., LaFemina, R. L. & Hayward, G. S. trans-activation and autoregulation of gene expression by the immediate-early region 2 gene products of human cytomegalovirus. J. Virol. 62, 1167–1179 (1988).
pubmed: 2831379
pmcid: 253124
doi: 10.1128/jvi.62.4.1167-1179.1988
Cherrington, J. M., Khoury, E. L. & Mocarski, E. S. Human cytomegalovirus ie2 negatively regulates alpha gene expression via a short target sequence near the transcription start site. J. Virol. 65, 887–896 (1991).
pubmed: 1846203
pmcid: 239829
doi: 10.1128/jvi.65.2.887-896.1991
Liu, B., Hermiston, T. W. & Stinski, M. F. A cis-acting element in the major immediate-early (IE) promoter of human cytomegalovirus is required for negative regulation by IE2. J. Virol. 65, 897–903 (1991).
pubmed: 1846204
pmcid: 239830
doi: 10.1128/jvi.65.2.897-903.1991
Spiegel, J. et al. G-quadruplexes are transcription factor binding hubs in human chromatin. Genome Biol. 22, 117 (2021).
pubmed: 33892767
pmcid: 8063395
doi: 10.1186/s13059-021-02324-z
Hammerschmidt, W. & Sugden, B. Replication of Epstein-Barr viral DNA. Cold Spring Harb. Perspect. Biol. 5, a013029 (2013).
pubmed: 23284049
pmcid: 3579399
doi: 10.1101/cshperspect.a013029
Zhang, Q., Holley-Guthrie, E., Ge, J. Q., Dorsky, D. & Kenney, S. The Epstein-Barr virus (EBV) DNA polymerase accessory protein, BMRF1, activates the essential downstream component of the EBV oriLyt. Virology 230, 22–34 (1997).
pubmed: 9126259
doi: 10.1006/viro.1997.8470
Gruffat, H., Renner, O., Pich, D. & Hammerschmidt, W. Cellular proteins bind to the downstream component of the lytic origin of DNA replication of Epstein-Barr virus. J. Virol. 69, 1878–1886 (1995).
pubmed: 7853529
pmcid: 188800
doi: 10.1128/jvi.69.3.1878-1886.1995
Fenouil, R. et al. CpG islands and GC content dictate nucleosome depletion in a transcription-independent manner at mammalian promoters. Genome Res. 22, 2399–2408 (2012).
pubmed: 23100115
pmcid: 3514669
doi: 10.1101/gr.138776.112
Hoshina, S. et al. Human origin recognition complex binds preferentially to G-quadruplex-preferable RNA and single-stranded DNA. J. Biol. Chem. 288, 30161–30171 (2013).
pubmed: 24003239
pmcid: 3798484
doi: 10.1074/jbc.M113.492504
Boos, D., Yekezare, M. & Diffley, J. F. Identification of a heteromeric complex that promotes DNA replication origin firing in human cells. Science 340, 981–984 (2013).
pubmed: 23704573
doi: 10.1126/science.1237448
Kumagai, A. & Dunphy, W. G. MTBP, the partner of Treslin, contains a novel DNA-binding domain that is essential for proper initiation of DNA replication. Mol. Biol. Cell 28, 2998–3012 (2017).
pubmed: 28877985
pmcid: 5662258
doi: 10.1091/mbc.e17-07-0448
Ryon, J. J. et al. The lytic origin of herpesvirus papio is highly homologous to Epstein-Barr virus ori-Lyt: evolutionary conservation of transcriptional activation and replication signals. J. Virol. 67, 4006–4016 (1993).
pubmed: 8389916
pmcid: 237768
doi: 10.1128/jvi.67.7.4006-4016.1993
Chen, W. F. et al. Molecular mechanistic insights into drosophila DHX36-Mediated G-quadruplex unfolding: a structure-based model. Structure 26, 403–415.e404 (2018).
pubmed: 29429875
doi: 10.1016/j.str.2018.01.008
Chen, M. C. et al. Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36. Nature 558, 465–469 (2018).
pubmed: 29899445
pmcid: 6261253
doi: 10.1038/s41586-018-0209-9
Tai-Schmiedel, J. et al. Human cytomegalovirus long noncoding RNA4.9 regulates viral DNA replication. PLoS Pathog. 16, e1008390 (2020).
pubmed: 32294138
pmcid: 7185721
doi: 10.1371/journal.ppat.1008390
Chung, W. C. et al. G-quadruplexes formed by Varicella-Zoster virus reiteration sequences suppress expression of glycoprotein C and regulate viral cell-to-cell spread. PLoS Pathog. 19, e1011095 (2023).
pubmed: 36630443
pmcid: 9873165
doi: 10.1371/journal.ppat.1011095
Xu, H. et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat. Commun. 8, 14432 (2017).
pubmed: 28211448
pmcid: 5321743
doi: 10.1038/ncomms14432
Westdorp, K. N. & Terhune, S. S. Impact of RNA polymerase I inhibitor CX-5461 on viral kinase-dependent and -independent cytomegalovirus replication. Antivir. Res. 153, 33–38 (2018).
pubmed: 29458130
doi: 10.1016/j.antiviral.2018.02.014
Pietras, Z. et al. Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria. Nat. Commun. 9, 2558 (2018).
pubmed: 29967381
pmcid: 6028389
doi: 10.1038/s41467-018-05007-9
Estep, K. N., Butler, T. J., Ding, J. & Brosh, R. M. G4-Interacting DNA helicases and polymerases: potential therapeutic targets. Curr. Med. Chem. 26, 2881–2897 (2019).
pubmed: 29149833
pmcid: 6663639
doi: 10.2174/0929867324666171116123345
Mendoza, O., Bourdoncle, A., Boule, J. B., Brosh, R. M. Jr. & Mergny, J. L. G-quadruplexes and helicases. Nucleic Acids Res. 44, 1989–2006 (2016).
pubmed: 26883636
pmcid: 4797304
doi: 10.1093/nar/gkw079
Wang, Y., Li, H., Tang, Q., Maul, G. G. & Yuan, Y. Kaposi’s sarcoma-associated herpesvirus ori-Lyt-dependent DNA replication: involvement of host cellular factors. J. Virol. 82, 2867–2882 (2008).
pubmed: 18199640
pmcid: 2259006
doi: 10.1128/JVI.01319-07
Dabral, P., Uppal, T. & Verma, S. C. G-quadruplexes of KSHV oriLyt play important roles in promoting lytic DNA replication. Microbiol. Spectr. 11, e0531622 (2023).
pubmed: 37800915
doi: 10.1128/spectrum.05316-22
Kwon, K. M., Oh, S. E., Kim, Y. E., Han, T. H. & Ahn, J. H. Cooperative inhibition of RIP1-mediated NF-kappaB signaling by cytomegalovirus-encoded deubiquitinase and inactive homolog of cellular ribonucleotide reductase large subunit. PLoS Pathog. 13, e1006423 (2017).
pubmed: 28570668
pmcid: 5469499
doi: 10.1371/journal.ppat.1006423
Huppert, J. L. & Balasubramanian, S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 33, 2908–2916 (2005).
pubmed: 15914667
pmcid: 1140081
doi: 10.1093/nar/gki609
Kim, Y. E. & Ahn, J. H. Role of the specific interaction of UL112-113 p84 with UL44 DNA polymerase processivity factor in promoting DNA replication of human cytomegalovirus. J. Virol. 84, 8409–8421 (2010).
pubmed: 20538862
pmcid: 2918997
doi: 10.1128/JVI.00189-10
Kim, E. T. et al. Analysis of human cytomegalovirus-encoded SUMO targets and temporal regulation of SUMOylation of the immediate-early proteins IE1 and IE2 during Infection. PLoS One 9, e103308 (2014).
pubmed: 25050850
pmcid: 4106884
doi: 10.1371/journal.pone.0103308
Park, M. Y. et al. Interactions among four proteins encoded by the human cytomegalovirus UL112-113 region regulate their intranuclear targeting and the recruitment of UL44 to prereplication foci. J. Virol. 80, 2718–2727 (2006).
pubmed: 16501081
pmcid: 1395424
doi: 10.1128/JVI.80.6.2718-2727.2006