SV40 and human tumours: myth, association or causality?


SV40 and human tumours: myth, association or causality?

Adi F. Gazdar, Janet S. Butel & Michele Carbone

Nature Reviews Cancer 2, 957-964 (December 2002)

doi:10.1038/nrc947

The simian virus 40 (SV40) genome is small (5.2 kb) and contains a limited coding capacity (see accompanying figure). It comprises three parts — a non-translated regulatory region of about 400 bp in size that contains the origin of replication (ori) and the promoters and enhancers that control replication; the early region that encodes the replication proteins (T Ag, t Ag and 17 kT protein) is expressed soon after the virus enters a cell; and the late region that encodes the capsid proteins (VP1, 2 and 3) and a maturation protein (agnoprotein), and is expressed efficiently only after viral DNA replication has begun.

SV40 and human tumours: myth, association or causality?

The transcriptional promoters and enhancers are located very close to the functional ori sequence. The early promoter contains three T Ag-binding sites, some of which overlap the TATA box element that directs the initiation of transcription. Immediately adjacent is a GC-rich cluster (21-bp repeats) that binds the transcription factor SP1. Further upstream is the enhancer region (72-bp element), which contains several transcription-factor-binding sites and acts to increase transcription initiation.

Viral transcription is mediated by cellular RNA polymerase II. Only small amounts of early transcripts are produced (a few hundred molecules per cell), whereas late transcripts are much more abundant (several hundred thousand copies per cell). Early and late transcription proceeds bidirectionally from near the ori, with the early and late transcripts being produced from opposite strands of the viral DNA. Alternative splicing of pre-messenger RNAs (pre-mRNAs) produces functional mRNAs.

T Ag is not a transcription factor per se, but it can autoregulate the early promoter as the replication cycle proceeds. When T Ag reaches a high enough concentration in the cell, it binds to viral DNA which might block the assembly of functional transcriptional complexes, repressing early transcription. T Ag indirectly contributes to the activation of SV40 late transcription in ways that are not clear, perhaps by stabilizing interactions among transcription factors.

Viral DNA replication requires a functional SV40 ori, T Ag protein with intact DNA-binding and helicase activities, and several cellular proteins involved in DNA synthesis. T Ag binds to specific sites in the SV40 ori, catalyses local unwinding of the viral DNA, and recruits cellular DNA replication proteins to the complex, including topoisomerase I, replication protein A (RPA) and DNA polymerases. The nature of cellular DNA polymerase primase from different species limits the host range of polyomaviruses. Both monkey and human proteins can replicate SV40 DNA. Topoisomerase II separates the newly joined replicated circular DNA daughter molecules.

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