Abstract
Polyadenylation occurs at numerous sites within 3’ untranslated
regions (3’ UTRs) but rarely within coding regions. How does Pol II
travel through long coding regions without generating poly(A) sites, yet
then permits promiscuous polyadenylation once it reaches the 3’ UTR? The
cleavage/polyadenylation (CpA) machinery preferentially associates with
3’ UTRs, but it is unknown how its recruitment is restricted to 3’ UTRs
during Pol II elongation. Unlike coding regions, 3’ UTRs have long
AT-rich stretches of DNA that may be important for restricting
polyadenylation to 3’ UTRs. Recognition of the 3’ UTR could occur at the
DNA (AT-rich), RNA (AU-rich), or RNA:DNA hybrid rU:dA- and/or
rA:dT-rich) level. Based on the nucleic acid critical for 3’
UTR recognition, there are three classes of models, not mutually
exclusive, for how the CpA machinery is selectively recruited to 3’
UTRs, thereby restricting where polyadenylation occurs: 1) RNA-based
models suggest that the CpA complex directly (or indirectly through one
or more intermediary proteins) binds long AU-rich stretches that are
exposed after Pol II passes through these regions. 2) DNA-based models
suggest that the AT-rich sequence affects nucleosome depletion or the
elongating Pol II machinery, resulting in dissociation of some
elongation factors and subsequent recruitment of the CpA machinery. 3)
RNA:DNA hybrid models suggest that preferential destabilization of the
Pol II elongation complex at rU:dA- and/or rA:dT-rich duplexes bridging
the nucleotide addition and RNA exit sites permits preferential
association of the CpA machinery with 3’ UTRs. Experiments to provide
evidence for one or more of these models are suggested.
