COTRANSCRIPTION AND INTERGENIC SPLICING OF HUMAN GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE AND INTERLEUKIN-11 RECEPTOR ALPHA-CHAIN GENES GENERATE A FUSION MESSENGER-RNA IN NORMAL-CELLS - IMPLICATION FOR THE PRODUCTION OF MULTIDOMAIN PROTEINS DURING EVOLUTION

In the past 10 years, much attention has been focused on transcription preinitiation complex formation as a target for regulating gene expre ssion, and other targets such as transcription termination complex ass emblage have been less intensively investigated. We established the ex istence of poly(A) site choice and fusion splicing of two adjacent gen es, galactose-1-phosphate uridylyl-transferase (GALT) and interleukin- 11 receptor alpha-chain (IL-11R alpha), in normal human cells. This 16 -kilobase (kb) transcription unit contains two promoters (the first on e is constitutive, and the second one, 8 kb downstream, is highly regu lated) and two cleavage/polyadenylation signals separated by 12 kb, Th e promoter from the GALT gene yields two mRNAs, a 1,4-kb mRNA encoding GALT and a 3-kb fusion mRNA when the first poly(A) site is spliced ou t and the second poly(A) is used, The 3-kb mRNA codes for a fusion pro tein of unknown function, containing part of the GALT protein and the entire IL-11R alpha protein. The GALT promoter/IL-11R alpha poly(A) tr anscript results from leaky termination and alternative splicing. This feature of RNA polymerase (pol) II transcription, which contrasts wit h efficient RNA pol I and pol III termination, may be involved, togeth er with chromosome rearrangements, in the generation of fusion protein s with multiple domains and would have major evolutionary implications in terms of natural processes to generate novel proteins with common motifs, Our results, together with accumulation of genomic information s, will stimulate new considerations and experiments in gene expressio n studies.