Kaposi sarcoma herpes virus latency associated nuclear antigen protein release the G2/M cell cycle blocks by modulating ATM/ATR mediated checkpoint pathway

Amit Kumar; Sushil Kumar Sahu; Suchitra Mohanty; Sudipta Chakrabarti; Santanu Maji; R Rajendra Reddy; Asutosh K Jha; Chandan Goswami; Chanakya N Kundu; Shanmugam Rajasubramaniam; Subhash C Verma; Tathagata Choudhuri

doi:10.1371/journal.pone.0100228

Kaposi sarcoma herpes virus latency associated nuclear antigen protein release the G2/M cell cycle blocks by modulating ATM/ATR mediated checkpoint pathway

PLoS One. 2014 Jun 27;9(6):e100228. doi: 10.1371/journal.pone.0100228. eCollection 2014.

Affiliations

¹ Division of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India.
² School of Biological Science, National Institute of Science Education and Research, Bhubaneswar, India.
³ School of Biotechnology, KIIT University, Bhubaneswar, India.
⁴ Department of Biotechnology, Regional Medical Research Centre for Tribals, Jabalpur, India.
⁵ Department of Microbiology and Immunology, University of Nevada, Reno, School of Medicine, Reno, Nevada, United States of America.
⁶ Division of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India; Department of Biotechnology, Siksha Vhabana, Visva Bharati, Santiniketan, Bolpur, India.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Viral / metabolism*
Antineoplastic Agents / pharmacology
Ataxia Telangiectasia Mutated Proteins / metabolism*
B-Lymphocytes / drug effects
B-Lymphocytes / metabolism
CDC2 Protein Kinase
Cell Cycle Checkpoints* / drug effects
Cell Cycle Checkpoints* / genetics
Cell Line
Cyclin-Dependent Kinases / chemistry
Cyclin-Dependent Kinases / genetics
Cyclin-Dependent Kinases / metabolism
Gene Expression Regulation
Herpesviridae Infections / metabolism*
Herpesvirus 8, Human / physiology*
Humans
Nocodazole / pharmacology
Nuclear Proteins / metabolism*
Phosphorylation
Protein Binding
Protein Interaction Domains and Motifs
Protein Transport
RNA Interference
RNA, Small Interfering / genetics
Signal Transduction* / drug effects

Substances

Antigens, Viral
Antineoplastic Agents
Nuclear Proteins
RNA, Small Interfering
latency-associated nuclear antigen
Ataxia Telangiectasia Mutated Proteins
CDC2 Protein Kinase
CDK1 protein, human
Cyclin-Dependent Kinases
Nocodazole

Grants and funding

AK, SKS, SM was supported by Council of Scientific and Industrial Research, Government of India. This work was supported by DBT through its RGYI grant, Department of Biotechnology, Government of India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.