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.
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DOI：
10.1093/nar/gkw038
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发表时间：
2016-05-05
影响因子：
14.9
通讯作者：
Verma SC
中科院分区：
文献类型：
--
作者：
Madireddy A;Purushothaman P;Loosbroock CP;Robertson ES;Schildkraut CL;Verma SC
卡波西肉瘤相关疱疹病毒（KSHV）通过在感染细胞中作为染色体外附加体持续存在并通过在分裂细胞中维持其基因组来建立终身潜伏感染。KSHV通过潜伏相关核抗原（拉娜）将其表观基因组拴系到宿主染色体上来实现这一点，LANA结合在病毒基因组的末端重复（TR）区。TR（富含GC的DNA元件）的序列分析鉴定了几个潜在的四链体富含G序列（QGRS）。由于四链体具有阻碍DNA复制的倾向，我们使用G-四链体稳定化合物来检查它们对潜伏DNA复制和病毒游离体的持久性的影响。我们的研究结果表明，这些G-四链体稳定化合物导致激活休眠的DNA复制起点，优先双向暂停的复制叉移动出TR区域，暗示的作用，丰富的G-TR的干扰附加型DNA复制。随着时间的推移，用PhenDC 3处理显示在感染的细胞中病毒附加体的损失。总体而言，这些数据显示G-四链体稳定化合物延缓复制叉的进展，导致DNA复制和附加型维持的减少。这些结果表明G-四链体稳定剂在治疗KSHV相关疾病中的潜在作用。
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.