title: Human DNA tumor viruses generate alternative reading frame proteins through repeat sequence recoding.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are human DNA tumor viruses that express nuclear antigens [latency-associated nuclear antigen 1 (LANA1) and Epstein-Barr nuclear antigen 1 (EBNA1)] necessary to maintain and replicate the viral genome. We report here that both LANA1 and EBNA1 undergo highly efficient +1/-2 programmed ribosomal frameshifting to generate previously undescribed alternative reading frame (ARF) proteins in their repeat regions. EBNA1(ARF) encodes a KSHV LANA-like glutamine- and glutamic acid-rich protein, whereas KSHV LANA1(ARF) encodes a serine/arginine-like protein. Repeat sequence recoding has not been described previously for human DNA viruses. Programmed frameshifting (recoding) to generate multiple proteins from one RNA sequence can increase the coding capacity of a virus, without incurring a selective penalty against increased capsid size. The presence of similar repeat sequences in cellular genes, such as huntingtin, suggests that a comparison of repeat recoding in virus and human systems may provide functional and mechanistic insights for both systems.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kwun
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Tuna
authors.initials: T
authors.lastname: Toptan
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033; and.
authors.forename: Suzane
authors.initials: S
authors.lastname: Ramos da Silva
authors.affiliation: School of Biochemistry, University College Cork, Cork, Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Atkins
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; yc70@pitt.edu psm9@pitt.edu.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; yc70@pitt.edu psm9@pitt.edu.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000378:metabolism*; D018965:Frameshifting, Ribosomal; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational; D017434:Protein Structure, Tertiary; D016364:Reading Frames / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid
chemical_list: D000956:Antigens, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D009687:Nuclear Proteins; C109540:latency-associated nuclear antigen; C417029:EBV-encoded nuclear antigen 1
keywords: EBV; HHV4; HHV8; POLY-Q; PRF