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

Shira Perez, Michael Gevor, Ateret Davidovich, Antony Kaspi, Katreena Yamin, Tom Domovich, Tomer Meirson, Avi Matityahu, Yehuda Brody, Salomon M. Stemmer, Assam El-Osta, Izhak Haviv, Itay Onn, Meital Gal-Tanamy

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)2455-2471
Number of pages17
JournalNucleic Acids Research
Volume47
Issue number5
DOIs
Publication statusPublished - 18 Mar 2019

Cite this

Perez, S., Gevor, M., Davidovich, A., Kaspi, A., Yamin, K., Domovich, T., ... Gal-Tanamy, M. (2019). Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions. Nucleic Acids Research, 47(5), 2455-2471. https://doi.org/10.1093/nar/gkz052
Perez, Shira ; Gevor, Michael ; Davidovich, Ateret ; Kaspi, Antony ; Yamin, Katreena ; Domovich, Tom ; Meirson, Tomer ; Matityahu, Avi ; Brody, Yehuda ; Stemmer, Salomon M. ; El-Osta, Assam ; Haviv, Izhak ; Onn, Itay ; Gal-Tanamy, Meital. / Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions. In: Nucleic Acids Research. 2019 ; Vol. 47, No. 5. pp. 2455-2471.
@article{baa230ba639b4bb78fd10eb22d28d1ea,
title = "Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions",
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.",
author = "Shira Perez and Michael Gevor and Ateret Davidovich and Antony Kaspi and Katreena Yamin and Tom Domovich and Tomer Meirson and Avi Matityahu and Yehuda Brody and Stemmer, {Salomon M.} and Assam El-Osta and Izhak Haviv and Itay Onn and Meital Gal-Tanamy",
year = "2019",
month = "3",
day = "18",
doi = "10.1093/nar/gkz052",
language = "English",
volume = "47",
pages = "2455--2471",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "5",

}

Perez, S, Gevor, M, Davidovich, A, Kaspi, A, Yamin, K, Domovich, T, Meirson, T, Matityahu, A, Brody, Y, Stemmer, SM, El-Osta, A, Haviv, I, Onn, I & Gal-Tanamy, M 2019, 'Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions' Nucleic Acids Research, vol. 47, no. 5, pp. 2455-2471. https://doi.org/10.1093/nar/gkz052

Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions. / Perez, Shira; Gevor, Michael; Davidovich, Ateret; Kaspi, Antony; Yamin, Katreena; Domovich, Tom; Meirson, Tomer; Matityahu, Avi; Brody, Yehuda; Stemmer, Salomon M.; El-Osta, Assam; Haviv, Izhak; Onn, Itay; Gal-Tanamy, Meital.

In: Nucleic Acids Research, Vol. 47, No. 5, 18.03.2019, p. 2455-2471.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dysregulation of the cohesin subunit RAD21 by Hepatitis C virus mediates host-virus interactions

AU - Perez, Shira

AU - Gevor, Michael

AU - Davidovich, Ateret

AU - Kaspi, Antony

AU - Yamin, Katreena

AU - Domovich, Tom

AU - Meirson, Tomer

AU - Matityahu, Avi

AU - Brody, Yehuda

AU - Stemmer, Salomon M.

AU - El-Osta, Assam

AU - Haviv, Izhak

AU - Onn, Itay

AU - Gal-Tanamy, Meital

PY - 2019/3/18

Y1 - 2019/3/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85062816896&partnerID=8YFLogxK

U2 - 10.1093/nar/gkz052

DO - 10.1093/nar/gkz052

M3 - Article

VL - 47

SP - 2455

EP - 2471

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 5

ER -