Abstract
The Kaposi's sarcoma-associated herpesvirus infects the human population and maintains latency stage of viral life cycle in a variety of cell types including cells of epithelial, mesenchymal and endothelial origin. The establishment of latent infection by KSHV requires the expression of an unique repertoire of genes among which latency associated nuclear antigen (LANA) plays a critical role in the replication of the viral genome. LANA regulates the transcription of a number of viral and cellular genes essential for the survival of the virus in the host cell. The present study demonstrates the disruption of the host G2/M cell cycle checkpoint regulation as an associated function of LANA. DNA profile of LANA expressing human B-cells demonstrated the ability of this nuclear antigen in relieving the drug (Nocodazole) induced G2/M checkpoint arrest. Caffeine suppressed nocodazole induced G2/M arrest indicating involvement of the ATM/ATR. Notably, we have also shown the direct interaction of LANA with Chk2, the ATM/ATR signalling effector and is responsible for the release of the G2/M cell cycle block.
Highlights
The Kaposi’s sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8 is a member of gammaherpes virus family and is etiologically associated with Kaposi’s sarcoma (KS) [1], primary effusion lymphoma (PEL) [2], and a subset of multicentric Castleman’s disease (MCD) [3]
This study demonstrates a novel function of the latency associated nuclear antigen (LANA), in releasing the G2/ M checkpoint arrest and its interaction with Chk2 to modulate the ataxia telangiectasia mutated (ATM)/ATM Rad3- related (ATR) signalling pathway
These results suggest that the KSHV positive cell are resistant to and/or reverse nocodazole induced G2/M block and allow cell cycle progression
Summary
The Kaposi’s sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8 is a member of gammaherpes virus family and is etiologically associated with Kaposi’s sarcoma (KS) [1], primary effusion lymphoma (PEL) [2], and a subset of multicentric Castleman’s disease (MCD) [3] This virus can infect a variety of human cell types such as cells of epithelial, mesenchymal and endothelial origin [4]. They maintain latency in host cells characterized by the persistence of the viral genome as circular episome with limited viral gene expressions such as viral FLICE inhibitory protein (v-FLIP), viral cyclin (v-cyclin) and latency associated nuclear antigen (LANA) [5,6]. LANA interacts with several transcription factors like E2F, Sp1, RBP-Jk, ATF4, Id-1, and Ets and causes their transcriptional activation [17,18,19,20,21,22], while it represses mSin3A, CBP, RING3, GSK-3b and p53 [12,23,24,25]
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