Promyelocytic leukemia nuclear bodies link the DNA damage repair pathway with hepatitis B virus replication: implications for hepatitis B virus exacerbation during chemotherapy and radiotherapy.
The mechanism responsible for hepatitis B virus (HBV) exacerbation during chemotherapy and radiotherapy remains unknown. We investigated whether the activation of DNA repair pathways influences HBV replication. The upregulation of the promyelocytic leukemia (PML) protein and its associated PML nuclear body (PML-NB) by chemotherapy and irradiation-induced DNA repair signaling correlated with the upregulation of HBV pregenomic transcription, HBV-core expression, and HBV DNA replication. The HBV-core protein and HBV DNA localized to PML-NBs, where they associated with PML and histone deacetylase 1 (HDAC1). Chemotherapy and radiotherapy affected the interactions between PML, HBV-core, and HDAC1. The enhanced protein-protein interaction between PML and HBV-core inhibited PML-mediated apoptosis and decreased PML-associated HDAC activity. The reversal of HDAC-mediated repression on the HBV covalently closed circular DNA basal core promoter resulted in the amplification of HBV-core and pregenomic expression. These results suggest that PML in PML-NBs links the DNA damage response with HBV replication and may cooperate with HBV-core and HDAC1 on the HBV covalently closed circular DNA basal core promoter to form a positive feedback loop for HBV exacerbation during chemotherapy and radiotherapy.
Chung
Yih-Lin
YL
Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan. ylchung@kfsyscc.org
Tsai
Tzung-Yuan
TY
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004270:DNA, Circular / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004279:DNA, Viral / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D064420:Drug-Related Side Effects and Adverse Reactions; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006509:Hepatitis B / Q000139:chemically induced / Q000235:genetics* / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D056284:Histone Deacetylase 1 / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000071156:Promyelocytic Leukemia Protein; D011878:Radiotherapy / Q000009:adverse effects; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014758:Viral Core Proteins / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects
D004270:DNA, Circular; D004279:DNA, Viral; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014758:Viral Core Proteins; C070576:PML protein, human; D056284:Histone Deacetylase 1