G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
Author
Advaitha MadireddyPurushothaman, Pravinkumar
Loosbroock, Christopher P.
Robertson, Erle S.
Schildkraut, Carl L.
Verma, Subhash C.
Date
2016Type
ArticleDOI
doi: 10.1093/nar/gkw038
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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 nu- clear 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 sta- bilizing compounds to examine their effect on la- tent DNA replication and the persistence of viral epi- somes. Our results showed that these G-quadruplex stabilizing compounds led to the activation of dor- mant 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 main- tenance. These results suggest a potential role for G-quadruplex stabilizers in the treatment of KSHV- associated diseases.
Permanent link
http://hdl.handle.net/11714/770Subject
VirologyAdditional Information
Rights | Creative Commons Attribution 4.0 United States |
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Rights Holder | © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. |