G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV

Kaposi's sarcoma associated herpesvirus (KSHV) establishes life-long latent infection by persisting as an extra-chromosomal episome in the infected cells and by maintaining its genome in dividing cells. KSHV achieves this by tethering its epigenome to the host chromosome by latency associated n...

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Bibliographic Details
Published in:Nucleic acids research Vol. 44; no. 8; pp. 3675 - 3694
Main Authors: Madireddy, Advaitha, Purushothaman, Pravinkumar, Loosbroock, Christopher P, Robertson, Erle S, Schildkraut, Carl L, Verma, Subhash C
Format: Journal Article
Language:English
Published: England Oxford University Press 05-05-2016
Subjects:
Cell Line
DNA Replication - drug effects
G-Quadruplexes - drug effects
Genome Integrity, Repair and
Genome, Viral - drug effects
HEK293 Cells
Herpesvirus
Herpesvirus 8, Human - drug effects
Herpesvirus 8, Human - genetics
Herpesvirus 8, Human - physiology
Humans
Kaposi's sarcoma-associated herpesvirus
Plasmids - drug effects
Porphyrins - pharmacology
Replication Origin
Terminal Repeat Sequences
Virus Latency
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Summary:Kaposi's sarcoma associated herpesvirus (KSHV) establishes life-long latent infection by persisting as an extra-chromosomal episome in the infected cells and by maintaining its genome in dividing cells. KSHV achieves this by tethering its epigenome to the host chromosome by latency associated nuclear antigen (LANA), which binds in the terminal repeat (TR) region of the viral genome. Sequence analysis of the TR, a GC-rich DNA element, identified several potential Quadruplex G-Rich Sequences (QGRS). Since quadruplexes have the tendency to obstruct DNA replication, we used G-quadruplex stabilizing compounds to examine their effect on latent DNA replication and the persistence of viral episomes. Our results showed that these G-quadruplex stabilizing compounds led to the activation of dormant origins of DNA replication, with preferential bi-directional pausing of replications forks moving out of the TR region, implicating the role of the G-rich TR in the perturbation of episomal DNA replication. Over time, treatment with PhenDC3 showed a loss of viral episomes in the infected cells. Overall, these data show that G-quadruplex stabilizing compounds retard the progression of replication forks leading to a reduction in DNA replication and episomal maintenance. These results suggest a potential role for G-quadruplex stabilizers in the treatment of KSHV-associated diseases.
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ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkw038