Abstract
Shugoshin-1 (Sgo1) protects the integrity of the centromeres, and H2A phosphorylation is critical for this process. The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromosomal instability (CIN), and its essential antigen LANA regulates Bub1. We show that LANA inhibits Bub1 phosphorylation of H2A and Cdc20, important for chromosome segregation and mitotic signaling. Inhibition of H2A phosphorylation at residue T120 by LANA resulted in dislocation of Sgo1, and cohesin from the centromeres. Arrest of Cdc20 phosphorylation also rescued degradation of Securin and Cyclin B1 at mitotic exit, and interaction of H2A, and Cdc20 with Bub1 was inhibited by LANA. The N-terminal nuclear localization sequence domain of LANA was essential for LANA and Bub1 interaction, reversed LANA inhibited phosphorylation of H2A and Cdc20, and attenuated LANA-induced aneuploidy and cell proliferation. This molecular mechanism whereby KSHV-induced CIN, demonstrated that the NNLS of LANA is a promising target for development of anti-viral therapies targeting KSHV associated cancers.
Highlights
Kaposi’s sarcoma-associated Herpesvirus, referred as human herpes virus 8 (KSHV/ HHV8), a tumor virus, has been documented to be a major contributor to human malignancies and lymphoproliferative disorders, including Kaposi’s sarcoma, Primary effusion lymphoma, and Multicentric Castleman’s disease
KSHV is a known oncogenic herpes virus associated with human malignancies and lymphoproliferative disorders, which includes Kaposi’s sarcoma, Primary effusion lymphoma, and Multicentric Castleman’s disease
The results showed a gradual decrease of cells which were arrested in mitosis, which corresponded with an increase in LANA expression levels (Fig 1A and 1B, and S1A Fig)
Summary
Kaposi’s sarcoma-associated Herpesvirus, referred as human herpes virus 8 (KSHV/ HHV8), a tumor virus, has been documented to be a major contributor to human malignancies and lymphoproliferative disorders, including Kaposi’s sarcoma, Primary effusion lymphoma, and Multicentric Castleman’s disease. Disruption of cell cycle regulation by KSHV leads to genome instability and contributes to the oncogenic process [3]. Kaposi’s sarcoma (KS) lesions and KSHV-infected primary effusion lymphoma cells have genome instabilities including chromosomal instability (CIN) [4,5,6]. Alteration of cell cycle progression is a major hallmark of tumorigenesis, and KSHV disrupts the G1 checkpoint through deregulation of the expression levels of p21, p16, p53, E2F-responsive genes, CDK6, Cyclin D, Cyclin E, and Cyclin A [10,11]. KSHV modulates the ATM/ATR signal pathway associated with the G2/M checkpoint through its interaction with Chk2 [12], resulting in release of the G2/M cell cycle block
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