The Locus of Epstein–Barr Virus Terminal Repeat Processing Is Bound with Enhanced Affinity by Sp1 and Sp3

Spain, Tammy A.; Sun, Ren; Miller, George

doi:10.1006/viro.1997.8770

Cited by 5 publications

(4 citation statements)

References 49 publications

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“…Whether this suppression is caused by LANA binding to TR needs to be further investigated in latently infected cells. Interestingly, the TR of EBV also contain Sp1 and Sp3 binding sites, and it has been suggested that these factors do not regulate transcription but might play a role in genome circularization following de novo infection (31,33).…”

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confidence: 99%

Characterization of the Minimal Replicator of Kaposi's Sarcoma-Associated Herpesvirus Latent Origin

Renne

2005

J Virol

104

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The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) binds to two sites within the 801-bp-long terminal repeat (TR) and is the only viral protein required for episomal maintenance. While two or more copies of TR are required for long-term maintenance, a single TR confers LANA-dependent origin activity on plasmid DNA. Deletion mapping revealed a 71-bp-long minimal replicator containing two distinctive sequence elements: LANA binding sites (LBS1/2) and an adjacent 29-to 32-bp-long GC-rich sequence which we termed the replication element. Furthermore, the transcription factor Sp1 can bind to TR outside the minimal replicator and contributes to TR's previously reported enhancer activity.Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma (KS) and two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman's disease (5,6,30). The 140-kbp KSHV long unique region encodes approximately 90 genes, which are flanked on both sides with 20 to 40 copies of 801-bp-long GC-rich terminal repeats (TR) (20,24,29). During latency, only a small subset of viral genes, including the latency-associated nuclear antigen (LANA), is expressed and the viral genome is maintained as multiple copies of episomal DNA (10,11,28,32). LANA is a functional homologue of origin binding proteins EBNA-1 from Epstein-Barr virus (EBV) and E2 from human papillomavirus (15,22). LANA is necessary and sufficient to support stable long-term episomal maintenance in dividing cells by (i) tethering viral episomes to cellular chromosomes (1,2,7,8,12,13,19,26) and (ii) supporting the initiation of DNA replication of TR-containing plasmids (15,17,23), presumably by bridging the viral origin of replication (ori) and the host cellular replication machinery. Using short-term replication assays, we have previously demonstrated that all cis-regulatory sequences required for LANA-dependent ori activity are located within a single copy of TR (17). By performing a detailed deletion analysis, we determined the minimal replicator within TR and showed that the transcription factor Sp1 can bind to at least two sites within TR and contributes to its previously described enhancer activity (13).Mapping the minimal replicator within TR. The TR unit is 801 bp long and 89% GC rich (20,29). LANA binds in a cooperative fashion to two sites (LBS1/2) in TR located between nucleotides (nt) 571 and 610, and both binding sites contribute to ori activity as determined by short-term replication assays (12, 17). Located directly upstream of LBS1/2 is an 89-bp highly GC-rich element adjacent to a 101-bp AT-rich region (Fig. 1A). AT-rich stretches are often found in origins of replication and are believed to function in DNA unwinding (4). We have previously reported that deletion of TR sequences from nt 1 to 482, including the AT-rich region, and nt 610 to 801 downstream of LBS1/2 does not decrease replication efficiency. In contrast, a deletion of the GC-rich region (up to nt 551) completely abo...

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confidence: 99%

Characterization of the Minimal Replicator of Kaposi's Sarcoma-Associated Herpesvirus Latent Origin

Renne

2005

J Virol

104

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“…[26][27][28][29] Moreover, recently it has been shown that this motif is contained within a 15 bp DNA region that binds a protein complex involved in recombinogenic reorganization of the Epstein-Barr virus genome. 30,31 Here, we show in a functional assay system that this sequence is indeed directly involved in recombination events.…”

Section: Discussionmentioning

confidence: 80%

Capture of a recombination activating sequence from mammalian cells

Olson

Dornburg

1999

Gene Ther

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We have developed a genetic trap for identifying revealed a putative recombination signal (CCCACCC). sequences that promote homologous DNA recombination.When this heptamer or an abbreviated form (CCCACC) The trap employs a retroviral vector that normally disables were reinserted into the vector, they stimulated vector itself after one round of replication. Insertion of defined repair and other DNA rearrangements. Mutant forms of DNA sequences into the vector induced the repair of a 300 these oligomers (eg CCCAACC or CCWACWS) did not. base pair deletion, which restored its ability to replicate.Our data suggest that the recombination events occurred Tests of random sequence libraries made in the vector within 48 h after transfection.

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“…Variation in the copy number of the terminal repeat elements may play a role in viral gene expression and binding of transcription factors such as Sp1 (Figure 2). The Sp1 transcription factor binds immediately adjacent to the cleavage site in the terminal repeat element generating the linear viral form [37], [38].…”

Section: Resultsmentioning

confidence: 99%

Paleo-Immunology: Evidence Consistent with Insertion of a Primordial Herpes Virus-Like Element in the Origins of Acquired Immunity

Dreyfus¹

2009

PLoS ONE

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BackgroundThe RAG encoded proteins, RAG-1 and RAG-2 regulate site-specific recombination events in somatic immune B- and T-lymphocytes to generate the acquired immune repertoire. Catalytic activities of the RAG proteins are related to the recombinase functions of a pre-existing mobile DNA element in the DDE recombinase/RNAse H family, sometimes termed the “RAG transposon”.Methodology/Principal FindingsNovel to this work is the suggestion that the DDE recombinase responsible for the origins of acquired immunity was encoded by a primordial herpes virus, rather than a “RAG transposon.” A subsequent “arms race” between immunity to herpes infection and the immune system obscured primary amino acid similarities between herpes and immune system proteins but preserved regulatory, structural and functional similarities between the respective recombinase proteins. In support of this hypothesis, evidence is reviewed from previous published data that a modern herpes virus protein family with properties of a viral recombinase is co-regulated with both RAG-1 and RAG-2 by closely linked cis-acting co-regulatory sequences. Structural and functional similarity is also reviewed between the putative herpes recombinase and both DDE site of the RAG-1 protein and another DDE/RNAse H family nuclease, the Argonaute protein component of RISC (RNA induced silencing complex).Conclusions/SignificanceA “co-regulatory” model of the origins of V(D)J recombination and the acquired immune system can account for the observed linked genomic structure of RAG-1 and RAG-2 in non-vertebrate organisms such as the sea urchin that lack an acquired immune system and V(D)J recombination. Initially the regulated expression of a viral recombinase in immune cells may have been positively selected by its ability to stimulate innate immunity to herpes virus infection rather than V(D)J recombination Unlike the “RAG-transposon” hypothesis, the proposed model can be readily tested by comparative functional analysis of herpes virus replication and V(D)J recombination.

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The Locus of Epstein–Barr Virus Terminal Repeat Processing Is Bound with Enhanced Affinity by Sp1 and Sp3

Cited by 5 publications

References 49 publications

Characterization of the Minimal Replicator of Kaposi's Sarcoma-Associated Herpesvirus Latent Origin

Characterization of the Minimal Replicator of Kaposi's Sarcoma-Associated Herpesvirus Latent Origin

Capture of a recombination activating sequence from mammalian cells

Paleo-Immunology: Evidence Consistent with Insertion of a Primordial Herpes Virus-Like Element in the Origins of Acquired Immunity

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