Role for the shelterin protein TRF2 in human herpesvirus 6A/B chromosomal integration


Autoři: Shella Gilbert-Girard aff001;  Annie Gravel aff001;  Vanessa Collin aff001;  Darren J. Wight aff002;  Benedikt B. Kaufer aff002;  Eros Lazzerini-Denchi aff003;  Louis Flamand aff001
Působiště autorů: Division of Infectious Disease and Immunity, CHU de Québec Research Center, Quebec City, Quebec, Canada aff001;  Institut für Virologie, Freie Universität Berlin, Berlin, Germany aff002;  Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff003;  Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada aff004
Vyšlo v časopise: Role for the shelterin protein TRF2 in human herpesvirus 6A/B chromosomal integration. PLoS Pathog 16(4): e32767. doi:10.1371/journal.ppat.1008496
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008496

Souhrn

Human herpesviruses 6A and 6B (HHV-6A/B) are unique among human herpesviruses in their ability to integrate their genome into host chromosomes. Viral integration occurs at the ends of chromosomes within the host telomeres. The ends of the HHV-6A/B genomes contain telomeric repeats that facilitate the integration process. Here, we report that productive infections are associated with a massive increase in telomeric sequences of viral origin. The majority of the viral telomeric signals can be detected within viral replication compartments (VRC) that contain the viral DNA processivity factor p41 and the viral immediate-early 2 (IE2) protein. Components of the shelterin protein complex present at telomeres, including TRF1 and TRF2 are also recruited to VRC during infection. Biochemical, immunofluorescence coupled with in situ hybridization and chromatin immunoprecipitation demonstrated the binding of TRF2 to the HHV-6A/B telomeric repeats. In addition, approximately 60% of the viral IE2 protein localize at cellular telomeres during infection. Transient knockdown of TRF2 resulted in greatly reduced (13%) localization of IE2 at cellular telomeres (p<0.0001). Lastly, TRF2 knockdown reduced HHV-6A/B integration frequency (p<0.05), while no effect was observed on the infection efficiency. Overall, our study identified that HHV-6A/B IE2 localizes to telomeres during infection and highlight the role of TRF2 in HHV-6A/B infection and chromosomal integration.

Klíčová slova:

Cell hybridization – DNA replication – DNA-binding proteins – Genomic signal processing – Probe hybridization – Repeated sequences – Telomeres – Viral replication


Zdroje

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