Posted Content10.21203/RS.3.RS-136834/V2
KSHV Episome Tethering Sites on Host Chromosomes: Regulation of Latency-Lytic Switch by the ChAHP complex
Ashish Kumar,Yuanzhi Lyu,Yuichi Yanagihashi,Chanikarn Chantarasrivong,Vladimir Majerciak,Michelle Salemi,Kang-Hsin Wang,Frank Y. S. Chuang,Ryan M. Davis,Clifford G. Tepper,Kazushi Nakano,Chie Izumiya,Michiko Shimoda,Ken-ichi Nakajima,Alexander A. Merleev,Zhi-Ming Zheng,Mel Campbell,Yoshihiro Izumiya +17 more
- 22 Sep 2021
TL;DR: A model in which elevated lncRNA expression determines the KSHV latency-lytic decision by regulating LANA/ChAHP DNA binding at inducible viral enhancers is proposed.
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Abstract:
Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the cell nucleus, but where KSHV episomal genomes are tethered and the mechanisms underlying KSHV lytic reactivation are unclear. Here, we study the nuclear microenvironment of KSHV episomes and show that the KSHV latency-lytic replication switch is regulated via viral long non-coding (lnc)RNA-CHD4 (chromodomain helicase DNA binding protein 4) interaction. KSHV episomes localize with a CHD4 complex, ChAHP, at epigenetically active genomic regions and tethers frequently near centromeric regions of host chromosomes. The ChAHP complex also occupies the 5’-region of a highly-inducible lncRNAs and terminal repeats of KSHV genome with latency-associated nuclear antigen (LANA). Viral lncRNA binding competes with CHD4 DNA binding, and KSHV reactivation is accompanied by the detachment of KSHV episomes from host chromosome docking sites We propose a model in which elevated lncRNA expression determines the KSHV latency-lytic decision by regulating LANA/ChAHP DNA binding at inducible viral enhancers.
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Citations
KSHV Topologically Associating Domains in Latent and Reactivated Viral Chromatin
Yoshihiro Izumiya
- 06 Apr 2022
TL;DR: A 3D genomic structural model for Kaposi's sarcoma-associated herpesvirus (KSHV) has been proposed in this article , which shows that the immediate early promoter region is localized on the periphery of the 3D viral genome during latency, while highly inducible non-coding RNA regions moved toward the inner space of the structure, resembling the configuration of a "bird cage" during reactivation.
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TL;DR: The interaction between LANA and the kinetochore proteins CENP-F and Bub1 is important for KSHV genome tethering and its segregation to new daughter cells, with Bub1 potentially playing a more critical role in the long-term persistence of the viral genome in the infected cell.
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Jianxin You,Viswanathan Srinivasan,Gerald V. Denis,William J. Harrington,Mary E. Ballestas,Kenneth M. Kaye,Peter M. Howley +6 more
TL;DR: It is found that KSHV LANA binds Brd4 in vivo and in vitro and that the binding is mediated by a direct protein-protein interaction between the ET (extraterminal) domain of Brd 4 and a carboxyl-terminal region of LANA previously implicated in chromosome binding.
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TL;DR: The Kaposi's sarcoma-associated herpesvirus (KSHV), also called human HSV 8 (HHV-8), was found to be an etiologic agent for this disease.