title: The Deacetylase Sirtuin 1 Regulates Human Papillomavirus Replication by Modulating Histone Acetylation and Recruitment of DNA Damage Factors NBS1 and Rad51 to Viral Genomes.
abstract: Human papillomaviruses (HPV) regulate their differentiation-dependent life cycles by activating a number of cellular pathways, such as the DNA damage response, through control of post-translational protein modification. Sirtuin 1 (SIRT1) is a protein deacetylase that modulates the acetylation of a number of cellular substrates, resulting in activation of pathways controlling gene expression and DNA damage repair. Our studies indicate that SIRT1 levels are increased in cells containing episomes of high-risk HPV types through the combined action of the E6 and E7 oncoproteins. Knockdown of SIRT1 in these cells with shRNAs impairs viral activities including genome maintenance, amplification and late gene transcription, with minimal effects on cellular proliferation ability. Abrogation of amplification was also seen following treatment with the SIRT1 deacetylase inhibitor, EX-527. Importantly, SIRT1 binds multiple regions of the HPV genome in undifferentiated cells, but this association is lost upon of differentiation. SIRT1 regulates the acetylation of Histone H1 (Lys26) and H4 (Lys16) bound to HPV genomes and this may contribute to regulation of viral replication and gene expression. The differentiation-dependent replication of high-risk HPVs requires activation of factors in the Ataxia Telangiectasia Mutated (ATM) pathway and SIRT1 regulates the recruitment of both NBS1 and Rad51 to the viral genomes. These observations demonstrate that SIRT1 is a critical regulator of multiple aspects of the high-risk HPV life cycle.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Erika S
authors.initials: ES
authors.lastname: Langsfeld
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bodily
authors.affiliation: Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Laimonis A
authors.initials: LA
authors.lastname: Laimins
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008018:Life Cycle Stages / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology; D030361:Papillomavirus Infections / Q000378:metabolism*; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D014161:Transduction, Genetic; D014779:Virus Replication / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C447939:SIRT1 protein, human; D056564:Sirtuin 1