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An RNA Polymerase Pause Site Is Associated with the Immunoglobulin µs Poly(A) Site

Department of Pathology and Laboratory Medicine, Department of Microbiology, Immunology, and Molecular Genetics, and the Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536

Received 24 January 2002/ Returned for modification 8 March 2002/ Accepted 3 May 2002

Immunoglobulin µ alternative RNA processing is regulated during B-cell maturation and requires balanced efficiencies of the competing splice (µm) and cleavage-polyadenylation (µs) reactions. When we deleted sequences 50 to 200 nucleotides beyond the µs poly(A) site, the µs/µm mRNA ratio decreased three- to eightfold in B, plasma, and nonlymphoid cells. The activity could not be localized to a smaller fragment but did function in heterologous contexts. Our data suggest that this region contains an RNA polymerase II pause site that enhances the use of the µs poly(A) site. First, known pause sites replaced the activity of the deleted fragment. Second, the µ fragment, when placed between tandem poly(A) sites, enhanced the use of the upstream poly(A) site. Finally, nuclear run-ons detected an increase in RNA polymerase loading just downstream from the µs poly(A) site, even when the poly(A) site was inactivated. When this µ fragment and another pause site were inserted 1 kb downstream from the µs poly(A) site, they no longer affected the mRNA expression ratio, suggesting that pause sites affect poly(A) site use over a limited distance. Fragments from the immunoglobulin A gene were also found to have RNA polymerase pause site activity.

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