2. Academic Validation
  3. Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions

Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions

  • Nucleic Acids Res. 2019 Mar 18;47(5):2455-2471. doi: 10.1093/nar/gkz052.
Shira Perez 1 2,  Michael Gevor 1 3,  Ateret Davidovich 1,  Antony Kaspi 4,  Katreena Yamin 3,  Tom Domovich 1,  Tomer Meirson 5,  Avi Matityahu 3,  Yehuda Brody 6,  Salomon M Stemmer 7,  Assam El-Osta 4 8,  Izhak Haviv 2,  Itay Onn 3,  Meital Gal-Tanamy 1
Affiliations

Affiliations

  • 1 Molecular Virology Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
  • 2 Cancer Personalized Medicine and Diagnostic Genomics Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
  • 3 Chromosome Instability and Dynamics Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
  • 4 Epigenetics in Human Health and Disease Laboratory, Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
  • 5 Cell Migration and Invasion Laboratory, Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
  • 6 The Broad institute of Harvard and MIT, Cambridge, MA, USA.
  • 7 Davidoff Center, Rabin Medical Center, Beilinson Campus, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 8 Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR.
PMID: 30698808 DOI: 10.1093/nar/gkz052
Abstract

Hepatitis C virus (HCV) Infection is the leading cause of chronic hepatitis, which often results in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV possesses an RNA genome and its replication is confined to the cytoplasm. Yet, Infection with HCV leads to global changes in gene expression, and chromosomal instability (CIN) in the host cell. The mechanisms by which the cytoplasmic virus affects these nuclear processes are elusive. Here, we show that HCV modulates the function of the Structural Maintenance of Chromosome (SMC) protein complex, cohesin, which tethers remote regions of chromatin. We demonstrate that Infection of hepatoma cells with HCV leads to up regulation of the expression of the RAD21 cohesin subunit and changes cohesin residency on the chromatin. These changes regulate the expression of genes associated with virus-induced pathways. Furthermore, siRNA downregulation of viral-induced RAD21 reduces HCV Infection. During mitosis, HCV Infection induces hypercondensation of chromosomes and the appearance of multi-centrosomes. We provide evidence that the underlying mechanism involves the viral NS3/4 protease and the cohesin regulator, WAPL. Altogether, our results provide the first evidence that HCV induces changes in gene expression and chromosome structure of infected cells by modulating cohesin.

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