Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Madireddy, Advaitha, Purushothaman, Pravinkumar, Loosbroock, Christopher P., Robertson, Erle S., Schildkraut, Carl L., Verma, Subhash C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856979/
https://www.ncbi.nlm.nih.gov/pubmed/26837574
http://dx.doi.org/10.1093/nar/gkw038
_version_ 1782430576171548672
author Madireddy, Advaitha
Purushothaman, Pravinkumar
Loosbroock, Christopher P.
Robertson, Erle S.
Schildkraut, Carl L.
Verma, Subhash C.
author_facet Madireddy, Advaitha
Purushothaman, Pravinkumar
Loosbroock, Christopher P.
Robertson, Erle S.
Schildkraut, Carl L.
Verma, Subhash C.
author_sort Madireddy, Advaitha
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4856979
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-48569792016-05-09 G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV Madireddy, Advaitha Purushothaman, Pravinkumar Loosbroock, Christopher P. Robertson, Erle S. Schildkraut, Carl L. Verma, Subhash C. Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2016-05-05 2016-02-02 /pmc/articles/PMC4856979/ /pubmed/26837574 http://dx.doi.org/10.1093/nar/gkw038 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Genome Integrity, Repair and Replication
Madireddy, Advaitha
Purushothaman, Pravinkumar
Loosbroock, Christopher P.
Robertson, Erle S.
Schildkraut, Carl L.
Verma, Subhash C.
G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
title G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
title_full G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
title_fullStr G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
title_full_unstemmed G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
title_short G-quadruplex-interacting compounds alter latent DNA replication and episomal persistence of KSHV
title_sort g-quadruplex-interacting compounds alter latent dna replication and episomal persistence of kshv
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856979/
https://www.ncbi.nlm.nih.gov/pubmed/26837574
http://dx.doi.org/10.1093/nar/gkw038
work_keys_str_mv AT madireddyadvaitha gquadruplexinteractingcompoundsalterlatentdnareplicationandepisomalpersistenceofkshv
AT purushothamanpravinkumar gquadruplexinteractingcompoundsalterlatentdnareplicationandepisomalpersistenceofkshv
AT loosbroockchristopherp gquadruplexinteractingcompoundsalterlatentdnareplicationandepisomalpersistenceofkshv
AT robertsonerles gquadruplexinteractingcompoundsalterlatentdnareplicationandepisomalpersistenceofkshv
AT schildkrautcarll gquadruplexinteractingcompoundsalterlatentdnareplicationandepisomalpersistenceofkshv
AT vermasubhashc gquadruplexinteractingcompoundsalterlatentdnareplicationandepisomalpersistenceofkshv