Nucleic Acids Research, Vol 26, Issue 3 721-729, Copyright © 1998 by Oxford University Press
M Antoniou, F Geraghty, J Hurst and F Grosveld
The second intron (betaIVS-II) of the human beta-globin gene is essential
for the accumulation of stable cytoplasmic mRNA and is implicated in
promoting efficient 3'-end formation. This report presents quantitative
comparisons between betaIVS-II mutants at physiological levels of
expression from within a natural chromatin context in vivo which further
defines it's function. In marked contrast to a beta-globin gene lacking a
second intron, two mutants defective in splicing (small size or a splice
donor mutation), still undergo essentially normal levels of 3'-end
formation and in the absence of exon skipping. Therefore, 3' cleavage of
beta-globin transcripts requires the presence of betaIVS-II sequences, but
not the splicing reaction. The placement of betaIVS-II in the IVS-I
position did not reduce the efficiency of 3' cleavage indicating that the
distance between the necessary element(s) in this intron and the
polyadenylation recognition site is not a crucial factor. Subsequent
placement of betaIVS-I in the intron II position, reduced the efficiency of
3'-end formation to only 16% of normal. A direct replacement of intron II
by the heterologous introns betaIVS-I or alpha-globin IVS-II, only
partially substitute (16 and 30% respectively) for betaIVS-II. Hybrid
introns show that efficient 3'-end formation is strongly enhanced by the
presence of the terminal 60 nt of betaIVS-II. These data imply that the
last intervening sequence of multiple intron containing genes is a
principal determinant of the efficiency of 3'-end formation and may act as
a post-transcriptional regulatory step in gene expression.
ARTICLES
Efficient 3'-end formation of human beta-globin mRNA in vivo requires sequences within the last intron but occurs independently of the splicing reaction
Department of Experimental Pathology, UMDS, Guy's Hospital, London Bridge, London SE1 9RT, UK. m.antoniou@umds.ac.uk
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