Dual roles for the telomeric repeats in chromosomally integrated human herpesvirus-6

Ohye, Tamae; Inagaki, Hidehito; Ihira, Masaru; Higashimoto, Yuki; Kato, Koji; Oikawa, Jun; Yagasaki, Hiroshi; Niizuma, Takahiro; Takahashi, Yoshiyuki; Kojima, Seiji; Yoshikawa, Tetsushi; Kurahashi, Hiroki

doi:10.1038/srep04559

Cited by 25 publications

(27 citation statements)

References 35 publications

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“…Even though the formal integration mechanism has yet to be demonstrated experimentally, sequencing of ciHHV-6A/B indicates that the TMR of the DR R of the genome is fused to the host chromosome telomeric repeats with loss of pac2 sequence from DR R . Such a structure is compatible with HR-mediated viral integration (5,30,31).…”

Section: Discussionmentioning

confidence: 69%

“…Analysis of the integrated virus genome revealed that the perfect TMR of the DR R region are fused to the host chromosome accompanied by a loss of the pac2 sequence, consistent with an integration mediated by HR between the viral TMR and the host telomere (5). At the other end of the viral genome, the pac1 region is also lost and additional telomeric repeats are added, suggesting that the TMR in DR L is a substrate for the generation of a new telomere (29)(30)(31).…”

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confidence: 93%

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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: 69%

mentioning

confidence: 93%

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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“…Upon cell replication and division, the 26-28 nucleotide pac1 sequences could erode until the TMR region is encountered. TMR could then serve as template for telomerase, as recently reported [33]. It remains unknown which cellular/viral proteins could participate in this BIR-dependent HHV-6 integration.…”

Section: Introductionmentioning

confidence: 88%

Chromosomally integrated HHV-6: impact on virus, cell and organismal biology

Kaufer

Flamand

2014

Current Opinion in Virology

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“…The integration occurs solely in telomeres and it has been shown that the telomeric sequences within the HHV-6A genome are essentials for efficient integration into chromosomes (4). Furthermore, the integrated virus has been sequenced and its orientation and missing sections are compatible with an integration by HR between the viral TMRs and the telomeres (11, 63, 64). Whether TRF2 plays a role in HHV-6A/B integrations remains to be shown.…”

Section: Discussionmentioning

confidence: 99%

Modulation and recruitment of TRF2 at viral telomeres during human herpesvirus 6A/B infection

Gilbert-Girard

Gravel

Collin

et al. 2019

Preprint

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21Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of host 22 chromosomes. The HHV-6A/B genomes contain telomeric repeats essential for integration. Whether HHV-6A/B 23 infections impact telomere homeostasis remains to be studied. We report that during infection, a massive 24 increase in telomeric signals is observed. Such telomeric signals are detected in viral replication compartments 25 (VRC) that colocalize with the viral IE2 and P41 proteins. Infection with HHV-6A mutants lacking telomeric 26repeats did not reproduce this phenotype. HHV-6A/B infections lead to increased expression of three shelterin 27 genes, TRF1, TRF2 and TPP1. TRF2 was recruited to VRC and binding to the HHV-6A/B telomeric repeats 28 demonstrated by chromatin immunoprecipitation and ELISA. Lastly, the HHV-6A IE2 protein colocalized with 29 shelterin proteins at telomeres during infection. In summary, HHV-6A/B infections results in an excess of 30 telomeric repeats that stimulates the expression of shelterin genes. TRF2 binds to viral telomeres during 31 infection and localizes with HHV-6A IE2 protein. Our results highlight a potential role for shelterin complex 32 proteins and IE2 during infection and possibly during integration of HHV-6A/B into host chromosomes. 33 34 35 36 3 37

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Dual roles for the telomeric repeats in chromosomally integrated human herpesvirus-6

Cited by 25 publications

References 35 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

Chromosomally integrated HHV-6: impact on virus, cell and organismal biology

Modulation and recruitment of TRF2 at viral telomeres during human herpesvirus 6A/B infection

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