AIM: To investigate whether hepatitis B virus (HBV) infection activates DNA damage response and DNA repair cofactors inhibit HBV infection and replication. METHODS: Human hepatocyte cell line HL7702 was studied. Immunoblotting was performed to test the expression of ataxia telangiectasia-mutated (ATM)-Rad3-related protein (ATR), p21 and the level of phosphorylation of Chk1, p53, H2AX, ATM in HBV-infected or non-infected-cells. Special short RNAi oligos was transfected to induce transient ATR knockdown in HL7702. ATR-ATM chemical inhibitors caffeine (CF) and theophylline (TP), or Chk1 inhibitor 7-hydroxystaurosporine (UCN01) was studied to determine whether they suppress cellular DNA damage response and MG132 inhibits proteasome. RESULTS: The ATR checkpoint pathway, responding to single-strand breaks in DNA, was activated in response to HBV infection. ATR knockdown cells decreased the HBV DNA yields, implying that HBV infection and replication could activate and exploit the activated DNA damage response. CF/TP or UCN01 reduced the HBV DNA yield by 70% and 80%, respectively. HBV abrogated the ATR-dependent DNA damage signaling pathway by degrading p21, and introduction of the p21 protein before HBV infection reduced the HBV DNA yield. Consistent with this result, p21 accumulation after MG132 treatment also sharply decreased the HBV DNA yield. CONCLUSION: HBV infection can be treated with therapeutic approaches targeting host cell proteins by inhibiting a cellular gene required for HBV replication or by restoring a response abrogated by HBV, thus providing a potential approach to the prevention and treatment of HBV infection.
AIM: To investigate whether hepatitis B virus (HBV) infection activates DNA damage response and DNA repair cofactors inhibit HBV infection and replication. METHODS:Human hepatocyte cell line HL7702 was studied. Immunoblotting was performed to test the expression of ataxia telangiectasia-mutated (ATM)-Rad3-related protein (ATR), p21 and the level of phosphorylation of Chk1, p53, H2AX, ATM in HBV-infected or non-infected-cells. Special short RNAi oligos was transfected to induce transient ATR knockdown in HL7702. ATR-ATM chemical inhibitors caffeine (CF) and theophylline (TP), or Chk1 inhibitor 7-hydroxystaurosporine (UCN01) was studied to determine whether they suppress cellular DNA damage response and MG132 inhibits proteasome. RESULTS: The ATR checkpoint pathway, responding to single-strand breaks in DNA, was activated in response to HBV infection. ATR knockdown cells decreased the HBV DNA yields, implying that HBV infection and replication could activate and exploit the activated DNA damage response. CF/TP or UCN01 reduced the HBV DNA yield by 70% and 80%, respectively. HBV abrogated the ATR-dependent DNA damage signaling pathway by degrading p21, and introduction of the p21 protein before HBV infection reduced the HBV DNA yield. Consistent with this result, p21 accumulation after MG132 treatment also sharply decreased the HBV DNA yield. CONCLUSION:HBV infection can be treated with therapeutic approaches targeting host cell proteins by inhibiting a cellular gene required for HBV replication or by restoring a response abrogated by HBV, thus providing a potential approach to the prevention and treatment of HBV infection.
Authors: Adriana Aguilar-Lemarroy; Patricio Gariglio; Noel J Whitaker; Sören T Eichhorst; Harald zur Hausen; Peter H Krammer; Frank Rösl Journal: Oncogene Date: 2002-01-10 Impact factor: 9.867
Authors: René Daniel; Gary Kao; Konstantin Taganov; James G Greger; Olga Favorova; George Merkel; Tim J Yen; Richard A Katz; Anna Marie Skalka Journal: Proc Natl Acad Sci U S A Date: 2003-04-04 Impact factor: 11.205
Authors: Q Liu; S Guntuku; X S Cui; S Matsuoka; D Cortez; K Tamai; G Luo; S Carattini-Rivera; F DeMayo; A Bradley; L A Donehower; S J Elledge Journal: Genes Dev Date: 2000-06-15 Impact factor: 11.361
Authors: Vassiliki Poulaki; Constantine S Mitsiades; Vassiliki Kotoula; Joseph Negri; Douglas McMillin; Joan W Miller; Nicholas Mitsiades Journal: Invest Ophthalmol Vis Sci Date: 2007-10 Impact factor: 4.799
Authors: Deborah J Kuhn; Qing Chen; Peter M Voorhees; John S Strader; Kevin D Shenk; Congcong M Sun; Susan D Demo; Mark K Bennett; Fijs W B van Leeuwen; Asher A Chanan-Khan; Robert Z Orlowski Journal: Blood Date: 2007-06-25 Impact factor: 22.113
Authors: Barbora Lubyova; Eva Tikalova; Kristyna Krulova; Jan Hodek; Ales Zabransky; Ivan Hirsch; Jan Weber Journal: Viruses Date: 2021-12-05 Impact factor: 5.048