Genome-wide analysis of G-quadruplexes in herpesvirus genomes

Biswas, Banhi; Kandpal, Manish; Jauhari, Utkarsh Kumar; Vivekanandan, Perumal

doi:10.1186/s12864-016-3282-1

Cited by 56 publications

(68 citation statements)

References 61 publications

(54 reference statements)

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“…Interestingly, BRACO-19 negatively affects genome-processing activities, such as replication and transcription of herpes simplex virus 1 (68), Epstein-Barr virus (69), and human immunodeficiency virus type 1 (70). Unlike these viruses, however, in silico analyses of the HHV-6A/B genomes indicate that potential G-quadruplex structures are located exclusively in the viral TMR and not within coding regions (70). BRACO-19 therefore is not expected to affect the expression of HHV-6A/B genes.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

Gilbert-Girard

Gravel

Artusi

et al. 2017

J Virol

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Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency (P Ͻ 0.002); in contrast, BRACO-19 had no effect on HHV-6 integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A.IMPORTANCE HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3= extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the current study, we have examined the effects of a G-quadruplex binding and stabilizing agent, BRACO-19, on HHV-6A chromosomal integration. By stabilizing G-quadruplex structures, BRACO-19 affects the ability of the telomerase complex to elongate telomeres. Our results indicate that BRACO-19 reduces the number of clones harboring integrated HHV-6A. This study is the first of its kind and suggests that telomerase activity is essential to restore a functional telomere of adequate length following HHV-6A integration.

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Section: Discussionmentioning

confidence: 99%

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

Gilbert-Girard

Gravel

Artusi

et al. 2017

J Virol

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“…Repeat regions in herpesviruses contain important regulatory elements for replication, packaging, latency, and reactivation [95,96]. The existence of RGQMs amplifies the G4 load of the genomes of HHVs manifold [44]. Such G4-forming iterative G-rich units also comprise the simple sequence repeats (SSRs) present in the noncoding regions of Nostoc sp.…”

Section: Discussionmentioning

confidence: 99%

“…Human herpesviruses (HHVs) are large double-stranded DNA (ds-DNA) viruses that infect a variety of tissues. In HHVs, putative promoter regions have higher G4 densities than the coding regions, suggesting a regulatory role for G4s in gene expression [44]. G4s in the promoters of UL2, UL24, and K18, all of which have previously established roles in virulence, were found to be negative regulators of promoter activity ( Figure 4A) [45][46][47][48].…”

Section: Conserva On Of G4s In S Cerevisiae Promotersmentioning

confidence: 96%

“…IE genes are expressed within a few hours of virus entry into the host cells. Interestingly, the regulatory regions of IE genes were particularly enriched for G4 motifs [44].…”

Section: Conserva On Of G4s In S Cerevisiae Promotersmentioning

confidence: 99%

“…The expression of latency-associated genes leads to heterochromatinization of the virus genome and the inhibition of proteins necessary for virus replication [58,59]. been noted in the eight HHVs [44]. Such G4-forming repeats have recently been identified to be functionally relevant in the latency of Kaposi's sarcoma-associated herpesvirus (KSHV) or HHV-8.…”

Section: Role In Virus Latencymentioning

confidence: 99%

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G-Quadruplexes: More Than Just a Kink in Microbial Genomes

Saranathan

Vivekanandan

2019

Trends in Microbiology

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G-quadruplexes (G4s) are noncanonical nucleic acid secondary structures formed by guanine-rich DNA and RNA sequences. In this review we aim to provide an overview of the biological roles of G4s in microbial genomes with emphasis on recent discoveries. G4s are enriched and conserved in the regulatory regions of microbes, including bacteria, fungi, and viruses. Importantly, G4s in hepatitis B virus (HBV) and hepatitis C virus (HCV) genomes modulate genes crucial for virus replication. Recent studies on Epstein-Barr virus (EBV) shed light on the role of G4s within the microbial transcripts as cis-acting regulatory signals that modulate translation and facilitate immune evasion. Furthermore, G4s in microbial genomes have been linked to radioresistance, antigenic variation, recombination, and latency. G4s in microbial genomes represent novel therapeutic targets for antimicrobial therapy.

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The Importance of Phosphates for DNA G‐Quadruplex Formation: Evaluation of Zwitterionic G‐Rich Oligodeoxynucleotides

Edwards

Stetsenko

et al. 2020

ChemBioChem

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A quaternary ammonium butylsulfonyl phosphoramidate group (N+) was designed to replace all the phosphates in a G‐rich oligodeoxynucleotide d(TG4T), resulting in a formally charge‐neutral zwitterionic N+TG4T sequence. We evaluated the effects of N+phosphate modifications on the structural, thermodynamic and kinetic properties of the parallel G‐quadruplexes (G4) formed by TG4T and compared them to the properties of the recently published phosphoryl guanidine d(TG4T) (PG‐TG4T). Using size‐exclusion chromatography, we established that, unlike PG‐TG4T, which exists as a mixture of complexes of different molecularity in solution, N+TG4T forms an individual tetramolecular complex. In contrast to PG modifications that destabilized G4s, the presence of N+ modifications increased thermal stability relative to unmodified [d(TG4T)]4. The initial stage of assembly of N+TG4T proceeded faster in the presence of Na+ than K+ions and, similarly to PG‐TG4T, was independent of the salt concentration. However, after complex formation exceeded 75 %, N+TG4T in solution with Na+showed slower association than with K+. N+TG4T could also form G4s in solution with Li+ions at a very low strand concentration (10 μM); something that has never been reported for the native d(TG4T). Charge‐neutral PG‐G4s can invade preformed native G4s, whereas no invasion was observed between N+and native G4s, possibly due to the increased thermal stability of [N+TG4T]4. The N+ modification makes d(TG4T) fully resistant to enzymatic digestion, which could be useful for intracellular application of N+‐modified DNA or RNA.

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Genome-wide analysis of G-quadruplexes in herpesvirus genomes

Cited by 56 publications

References 61 publications

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

G-Quadruplexes: More Than Just a Kink in Microbial Genomes

The Importance of Phosphates for DNA G‐Quadruplex Formation: Evaluation of Zwitterionic G‐Rich Oligodeoxynucleotides

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