Distinct Sets of Adjacent Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1/A2 Binding Sites Control 5′ Splice Site Selection in the hnRNP A1 mRNA Precursor

In the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 pre-mRNA, different regions in the introns flanking alternative exon 7B have been implicated in the production of the A1 and A1B mRNA splice isoforms. Among these, the CE1a and CE4 elements, located downstream of common exon 7 and alternative exon 7B, respectively, are bound by hnRNP A1 to promote skipping of exon 7Bin vivo and distal 5′ splice site selection in vitro. Here, we report that CE1a is flanked by an additional high affinity A1 binding site (CE1d). In a manner similar to CE1a, CE1d affects 5′ splice site selection in vitro. Consistent with a role for hnRNP A1 in the activity of CE1d, a mutation that abrogates A1 binding abolishes distal 5′ splice site activation. Moreover, the ability of CE1d to stimulate distal 5′ splice site usage is lost in an HeLa extract depleted of hnRNP A/B proteins, and the addition of recombinant A1 restores the activity of CE1d. Notably, distal 5′ splice site selection mediated by A1 binding sites is not compromised in an extract prepared from mouse cells that are severely deficient in hnRNP A1 proteins. In this case, we show that hnRNP A2 compensates for the A1 deficiency. Further studies with the CE4 element reveal that it also consists of two distinct portions (CE4m and CE4p), each one capable of promoting distal 5′ splice site use in an hnRNP A1-dependent manner. The presence of multiple A1/A2 binding sites downstream of common exon 7 and alternative exon 7B probably plays an important role in maximizing the activity of hnRNP A1/A2 proteins. In the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 pre-mRNA, different regions in the introns flanking alternative exon 7B have been implicated in the production of the A1 and A1B mRNA splice isoforms. Among these, the CE1a and CE4 elements, located downstream of common exon 7 and alternative exon 7B, respectively, are bound by hnRNP A1 to promote skipping of exon 7Bin vivo and distal 5′ splice site selection in vitro. Here, we report that CE1a is flanked by an additional high affinity A1 binding site (CE1d). In a manner similar to CE1a, CE1d affects 5′ splice site selection in vitro. Consistent with a role for hnRNP A1 in the activity of CE1d, a mutation that abrogates A1 binding abolishes distal 5′ splice site activation. Moreover, the ability of CE1d to stimulate distal 5′ splice site usage is lost in an HeLa extract depleted of hnRNP A/B proteins, and the addition of recombinant A1 restores the activity of CE1d. Notably, distal 5′ splice site selection mediated by A1 binding sites is not compromised in an extract prepared from mouse cells that are severely deficient in hnRNP A1 proteins. In this case, we show that hnRNP A2 compensates for the A1 deficiency. Further studies with the CE4 element reveal that it also consists of two distinct portions (CE4m and CE4p), each one capable of promoting distal 5′ splice site use in an hnRNP A1-dependent manner. The presence of multiple A1/A2 binding sites downstream of common exon 7 and alternative exon 7B probably plays an important role in maximizing the activity of hnRNP A1/A2 proteins. mRNA precursor heterogeneous nuclear ribonucleoprotein nucleotide(s) glutathione S-transferase rA2, and rA1B, recombinant A1, A2, and A1B, respectively The alternative splicing of mRNA precursors (pre-mRNAs)1 is a major contributor to the diversity of the mammalian proteome (1Lander E.S. Linton L.M. Birren B. Nusbaum C. Zody M.C. Baldwin J. Devon K. Dewar K. Doyle M. FitzHugh W. Funke R. Gage D. Harris K. Heaford A. Howland J. et al.Nature. 2001; 409: 860-921Crossref PubMed Scopus (17994) Google Scholar, 2Graveley B.R. Trends Genet. 2001; 17: 100-107Abstract Full Text Full Text PDF PubMed Scopus (942) Google Scholar, 3Croft L. Schandorff S. Clark F. Burrage K. Arctander P. Mattick J.S. Nat. Genet. 2000; 24: 340-341Crossref PubMed Scopus (179) Google Scholar). The control of splice site selection therefore has profound implications in the production of protein isoforms with different functions. Recent progress in uncovering the molecular strategies that control alternative splicing has led to the identification of many types of sequence elements that influence either positively or negatively the selection of the alternative splice sites. Exonic splicing enhancers are bound by specific members of the SR protein family that can enforce the use of weak 5′ and 3′ splice sites (reviewed in Ref. 4Graveley B.R. RNA. 2000; 6: 1197-1211Crossref PubMed Scopus (884) Google Scholar). Enhancer elements have also been described in the introns flanking some alternative exons (5Cooper T.A. Mol. Cell. Biol. 1998; 18: 4519-4525Crossref PubMed Scopus (43) Google Scholar, 6Huh G.S. Hynes R.O. Mol. Cell. Biol. 1993; 13: 5301-5314Crossref PubMed Scopus (57) Google Scholar, 7McCullough A.J. Berget S.M. Mol. Cell. Biol. 1997; 17: 4562-4571Crossref PubMed Scopus (185) Google Scholar, 8Mühlemann O. Yue B.G. Petersen-Mahrt S. Aküsjarvi G. Mol. Cell. Biol. 2000; 20: 2317-2325Crossref PubMed Scopus (20) Google Scholar, 9Ryan K.J. Cooper T.A. Mol. Cell. Biol. 1996; 16: 4014-4023Crossref PubMed Scopus (82) Google Scholar). Other types of proteins, including members of the hnRNP F/H family of proteins, can bind specifically to intron or exon control elements and hence can contribute to enhancer activity (10Black D.L. Cell. 1992; 69: 795-807Abstract Full Text PDF PubMed Scopus (148) Google Scholar, 11Min H. Chan R.C. Black D.L. Genes Dev. 1995; 9: 2659-2671Crossref PubMed Scopus (171) Google Scholar, 12Min H. Turck C.W. Nikolic J.M. Black D.L. Genes Dev. 1997; 11: 1023-1036Crossref PubMed Scopus (280) Google Scholar, 13Caputi M. Zahler A.M. EMBO J. 2002; 21: 845-855Crossref PubMed Scopus (103) Google Scholar, 14Caputi M. Zahler A.M. J. Biol. Chem. 2001; 276: 43850-43859Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). Elements that reduce the use of a neighboring splice site are also important in the control of splice site selection. In many cases, the activity of splicing silencers can be mediated by proteins that inhibit specific steps of splice site recognition or spliceosome assembly. A frequent example of this kind of splicing control in mammals involves the polypyrimidine tract-binding protein, which binds to some 3′ splice sequences and prevents U2AF binding (15Southby J. Gooding C. Smith C.W. Mol. Cell. Biol. 1999; 19: 2699-2711Crossref PubMed Google Scholar, 16Lin C.H. Patton J.G. RNA. 1995; 1: 234-245PubMed Google Scholar, 17Singh R. Valcárcel J. Green M.R. Science. 1995; 268: 1173-1176Crossref PubMed Scopus (466) Google Scholar, 18Chan R.C. Black D.L. Mol. Cell. Biol. 1997; 17: 4667-4676Crossref PubMed Google Scholar, 19Ashiya M. Grabowski P.J. RNA. 1997; 3: 996-1015PubMed Google Scholar). Other examples uncovered in mammalian pre-mRNAs include the binding of the SR proteins ASF/SF2 and SRp30c upstream of the branch site in the adenovirus IIIa pre-mRNA and the hnRNP A1 pre-mRNA, respectively (20Simard M.J. Chabot B. Mol. Cell. Biol. 2002; 22: 4001-4010Crossref PubMed Scopus (51) Google Scholar, 21Kanopka A. Mühlemann O. Aküsjarvi G. Nature. 1996; 381: 535-538Crossref PubMed Scopus (207) Google Scholar). The mechanisms by which inhibition occurs in these cases appear different, since ASF/SF2 prevents U2 snRNP binding in the adenoviral pre-mRNA, whereas SRp30c does not prevent the assembly of a U2-containing complex on the downstream 3′ splice site (21Kanopka A. Mühlemann O. Aküsjarvi G. Nature. 1996; 381: 535-538Crossref PubMed Scopus (207) Google Scholar, 22Simard M.J. Chabot B. Mol. Cell. Biol. 2000; 20: 7353-7362Crossref PubMed Scopus (14) Google Scholar). Members of the family of core hnRNP A/B proteins have also been identified as factors involved in the modulation of splice site selection. Using model pre-mRNAs carrying competing 5′ splice sites, important shifts toward distal 5′ splice sites can be obtained by the addition of purified or recombinant hnRNP A1 to a HeLa nuclear extract (23Mayeda A. Krainer A.R. Cell. 1992; 68: 365-375Abstract Full Text PDF PubMed Scopus (588) Google Scholar, 24Mayeda A. Munroe S.H. Cáceres J.F. Krainer A.R. EMBO J. 1994; 13: 5483-5495Crossref PubMed Scopus (280) Google Scholar). The Drosophila hrp48 protein, which is similar to hnRNP A1, is required in collaboration with P-element somatic inhibitor and the U1 snRNP to repress splicing of the P-element pre-mRNA in somatic tissues (25Hammond L.E. Rudner D.Z. Kanaar R. Rio D.C. Mol. Cell. Biol. 1997; 17: 7260-7267Crossref PubMed Scopus (59) Google Scholar). hnRNP A1 can elicit exon skipping, but not all pre-mRNAs are responsive to variations in the concentration of hnRNP A1 in vitro (26Mayeda A. Helfman D.M. Krainer A.R. Mol. Cell. Biol. 1993; 13: 2993-3001Crossref PubMed Scopus (202) Google Scholar). A1 can also negatively affect the use of 3′ splice sites in a variety of exons including the alternative exon of fibroblast growth factor receptor 2 gene (27Del Gatto-Konczak F. Olive M. Gesnel M.C. Breathnach R. Mol. Cell. Biol. 1999; 19: 251-260Crossref PubMed Scopus (199) Google Scholar), the tat and vpr exons of the human immunodeficiency virus M. A. Krainer A.R. Zahler A.M. EMBO J. 1999; 18: PubMed Scopus Google Scholar, A. Krainer A.R. J. 2001; PubMed Scopus Google Scholar, S. J. J. EMBO J. 2001; 20: PubMed Scopus Google Scholar), and the exon of the gene M. S. H. P. H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H. H. P. EMBO J. 1998; 17: PubMed Scopus Google Scholar). Consistent with the that A1 can specific elements G. EMBO J. 1994; 13: PubMed Scopus Google Scholar), of the that have been to hnRNP A1 in pre-mRNAs are on ability to with specific In all cases to the hnRNP A1 splice A1B, the A2 protein, and splicing can A1 in 5′ splice site and 3′ splice site selection in vitro A. Munroe S.H. Cáceres J.F. Krainer A.R. EMBO J. 1994; 13: 5483-5495Crossref PubMed Scopus (280) Google Scholar, M. A. Krainer A.R. Zahler A.M. EMBO J. 1999; 18: PubMed Scopus Google Scholar, A. Krainer A.R. J. 2001; PubMed Scopus Google Scholar). have that hnRNP A1 can the alternative splicing of pre-mRNA binding to sequences in the introns flanking alternative exon The CE1a element downstream of exon 7 and the CE4 sequence downstream of alternative exon 7B can promote distal 5′ splice site selection in an A1-dependent manner B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar, M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar). CE1a and CE4 the sequence which the A1 binding site obtained by selection of of sequences G. EMBO J. 1994; 13: PubMed Scopus Google Scholar). these high affinity A1 binding sites promote shifts in 5′ splice site in on splicing is not with in U1 nuclear ribonucleoprotein binding to the competing 5′ splice sites B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). have that the by which hnRNP A1 5′ splice site selection in this involves an bound A1 an that the 5′ splice site in a and in the of splice sites M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar, S. M.J. M. Chabot B. Recent Dev. Mol. Cell. Biol. 2000; 1: Scholar, B. C. S. M.J. P. in and Scholar). Here, we have uncovered additional elements capable of promoting distal 5′ splice site selection in vitro. Notably, we that sequences flanking CE1a and different portions of CE4 can with hnRNP that control elements promoting distal 5′ splice site in the hnRNP A1 pre-mRNA are in of A1 binding sites. the of hnRNP A1/A2 proteins and stimulate or the in pre-mRNA The described B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). and to the and described in Ref. B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google and by to the mouse sequences of portions of site of and described in Ref. M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google to the mouse sequence the site downstream of exon 7 and site downstream of exon 7B of by and by of with the from and by the site of The CE1d, and the site of to and and described M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar). from with for which obtained by with and with in the presence of and CE1d, and from and with and CE1a and from and and as as described in Ref. B. D. S. and nuclear prepared 11: PubMed Scopus Google and in splicing as described B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). to and a concentration of In all splicing we have and to splicing each 5′ splice The that these the pre-mRNA a of splicing pre-mRNA mRNA or the use of which the distal 5′ exon and the distal mRNA to the A2, and A1B proteins purified a as described in and Chabot S. Chabot B. 2001; PubMed Scopus Google Scholar). in A in the presence of and The proteins from the with The purified proteins The concentration of the recombinant proteins by of as a The for in a splicing B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google and on The rA2, and proteins to the and to on for to the addition of and The on in The of hnRNP proteins from nuclear as described in et M. A. Krainer A.R. Zahler A.M. EMBO J. 1999; 18: PubMed Scopus Google Scholar). of to a sequence CE1a for from in a and The to of the The with of and as a The which by the of of the to of the of HeLa nuclear extract and with of for The and the to a of the The with of The bound proteins from the with of of nuclear extract and proteins from the CE1a on to and for the presence of hnRNP a a sequence by these proteins by a of and proteins the to the The element is located in the intron downstream of common exon 7 in the hnRNP A1 is required for skipping of alternative exon 7B in vivo and distal 5′ splice site use the 5′ splice sites of exon 7 and exon 7B in a model pre-mRNA in vitro B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). have that a is for a of the of on 5′ splice site selection B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). CE1a does not the activity of the additional sequences also be promoting distal 5′ splice site these we the 3′ of the two 5′ splice sites in model the of and distal 5′ splice site use can be by the production of of a pre-mRNA in a nuclear extract and the on a In with the control pre-mRNA, of in a HeLa extract that the use of the distal 5′ splice site as by an in by the use of this site The of the with the of CE1a with the element a of 5′ splice site use the sequence that for the we two and a on 5′ splice site in splicing to the distal 5′ splice site and A of and CE1d that CE1d, but not splicing toward the distal 5′ splice site 7 and that the CE1d element sequences that can promote distal 5′ splice site selection in vitro as as the described CE1a we a of that CE1a and CE1d we that the of the two elements 5′ splice site selection to a that with the obtained with the element with the activity of in HeLa from the of CE1a and CE1d. hnRNP A1 has been implicated in the activity of CE1a, we hnRNP A1 also involved in the activity of CE1d. we the ability of hnRNP A1 to with CE1d by a of a recombinant protein The for this is and sequences by the CE1d on 5′ splice site it as a control in of the CE1d with CE1d but not with a specific of with CE1d. The that recombinant A1 protein can specifically with CE1d that this be required for the in 5′ splice site selection vitro. this we the CE1d element and on 5′ splice site selection in a HeLa nuclear The are in and in a of the pre-mRNA for CE1d in pre-mRNA distal 5′ splice site in a manner similar to in the The of the in CE1d not the activity of the element and with to distal 5′ splice site a splicing that similar to the obtained in the of CE1d with the the sequence of CE1d for binding by hnRNP In with a similar the sequence which bound by not bound by The A1 binding and the of distal 5′ splice site is with the that A1 is involved in the activity of CE1d. that hnRNP A1 the activity of CE1d, we the of hnRNP A1 from a HeLa nuclear extract by affinity carrying a high affinity binding site for hnRNP The CE1a to and in the presence of a HeLa nuclear The and as the depleted nuclear a that the core hnRNP A1, A2, and A1B proteins that the of these hnRNP proteins been from the nuclear extract hnRNP A1, A2, and A1B proteins in the bound to CE1a and A nuclear extract also prepared by a HeLa nuclear extract on a RNA. The extract the core hnRNP A/B proteins and in the bound and The and for activity a pre-mRNA have that 5′ splice site usage on this pre-mRNA can be from the distal to the site by the addition of an of carrying A1 binding sites and that with restores distal 5′ splice site use M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar). distal 5′ splice site use in the extract the 5′ splice site in the extract with a role for hnRNP A/B proteins in the activity of pre-mRNA to the 5′ splice site in the that these proteins also be required for the activity of CE1d The addition of of to the extract splicing toward the distal site in a manner the concentration the addition of to the pre-mRNA 5′ splice site use and the distal 5′ splice site In the concentration of 5′ splice site use the for the control pre-mRNA the of a pre-mRNA CE1d to the with that hnRNP A1 can the activity of CE1d. hnRNP A1 is for the activity of CE1a and CE1d, we splicing in an extract prepared from a mouse to be severely deficient in hnRNP A1 protein The of A1 and A1B has been the has a M.R. Chabot A. A. Mol. Cell. Biol. 1992; PubMed Scopus Google Scholar, S. Chabot B. S. A. 1994; PubMed Scopus Google Scholar). to in a HeLa extract and CE1a distal 5′ splice site in a nuclear extract prepared from cells 2 and with also splicing in a nuclear extract prepared from a of the which is for hnRNP A1 S. Chabot B. S. A. 1994; PubMed Scopus Google Scholar). The of distal 5′ splice site of the pre-mRNA in the and in the that cells a that hnRNP A1, to and shifts in 5′ splice site selection. that the hnRNP A2 protein can hnRNP A1 in ability to promote distal 5′ splice site vitro A. Munroe S.H. Cáceres J.F. Krainer A.R. EMBO J. 1994; 13: 5483-5495Crossref PubMed Scopus (280) Google Scholar). A2 and splice hnRNP can also A1 of a 3′ splice site is with high affinity A1 binding sites M. A. Krainer A.R. Zahler A.M. EMBO J. 1999; 18: PubMed Scopus Google Scholar, A. Krainer A.R. J. 2001; PubMed Scopus Google Scholar, S. J. J. EMBO J. 2001; 20: PubMed Scopus Google Scholar). cells hnRNP A2 and these proteins for the of A1 and A1B in affinity to hnRNP A2 and proteins from the nuclear extract not The of from the nuclear extract with an to the distal 5′ splice site with the pre-mRNA and that hnRNP A2 for A1 in the activity mediated by CE1d, we of recombinant or to the nuclear the the addition of or 5′ splice site use on the control pre-mRNA and and and The for the of pre-mRNA splicing by and in the mouse extract is the addition of and or on distal 5′ splice site use on the In the of and on the pre-mRNA a in use and an in distal splice site selection 7 and and and that hnRNP A2 can also the activity in 5′ splice site selection. hnRNP A2 is for the of a splicing in the The ability of hnRNP A2 to bind specifically to CE1d by a hnRNP A2 bound to CE1d but to Moreover, bound to the CE1d but the binding to the sequence A binding with recombinant A1B also specific binding to CE1d and binding to to CE1d can be bound by A1, A1B, or The use of recombinant A1B also a of distal 5′ splice site use in a manner in hnRNP not we have not hnRNP the splice of A2, we this protein to a similar binding it is also depleted from a HeLa extract a CE1a Moreover, have that also a that is similar to hnRNP A1 in splice site selection A. Munroe S.H. Cáceres J.F. Krainer A.R. EMBO J. 1994; 13: 5483-5495Crossref PubMed Scopus (280) Google Scholar, M. A. Krainer A.R. Zahler A.M. EMBO J. 1999; 18: PubMed Scopus Google Scholar). that the CE4 element downstream of alternative exon 7B a high affinity A1 binding CE4 distal 5′ splice site selection in vitro and exon 7B skipping in M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar). CE4 the sequence which is also in CE1a and which to be important for A1 binding and the activity of CE1a B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). elements that can distal 5′ splice site we a similar in we the in vitro splicing of pre-mRNAs carrying either CE4 or a the that the sequence we a in the of distal 5′ splice site use 2 with the that the sequence to the activity of CE4 on 5′ splice site selection. the the of CE4 as as CE1a promoting distal 5′ splice site selection that can also promote distal 5′ splice site selection in vitro. have that is not bound by recombinant hnRNP A1 in a M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar). we the binding with recombinant proteins that been prepared a high S. Chabot B. 2001; PubMed Scopus Google Scholar), we that bind to The that A1 does not with the control that binding to is specific the of A1 in the activity of we that been depleted of A/B proteins by affinity The control pre-mRNA to the 5′ splice site in a extract or in the extract and and the addition of on 5′ splice site selection the and In whereas the pre-mRNA to the distal site in the extract distal splicing in the extract Moreover, the addition of to the extract the of distal 5′ splice site use to an that with the in the extract that can also promote distal 5′ splice site in an A1-dependent manner. the activity of CE4 to CE1a and probably the that it distinct A1 binding sites. The activity of the identified and CE4 elements can be in each to capable of promoting distal 5′ splice site selection in vitro. is of CE1a and CE1d, each bound by members of the hnRNP A/B family of proteins. the activity of CE4 on 5′ splice site selection can be and each bound by hnRNP A1 or hnRNP A1 and A2 can the or in 5′ splice site selection in that been depleted of hnRNP A/B proteins. The A1 binding sites in CE1a and are and to a to the A1 binding site sequence obtained by selection from a of sequences G. EMBO J. 1994; 13: PubMed Scopus Google Scholar). In the sequence for the binding of A1 and A2 to CE1d and is the sequences and we have that the CE1a A1 binding and abrogates activity B. M. H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). a be with A1 CE1d also a variety of sequences that or the A1 binding of the that one of these sites CE1d activity Notably, CE1d and the sequence and Moreover, a mutation that these two regions affects the of additional A1/A2 binding sites in CE1d and The of hnRNP A/B binding sites in be for to an in the concentration of A/B proteins stimulate the of hnRNP A/B proteins. the of A1/A2 binding to these sites be important the concentration of A1/A2 proteins a is many additional of this of A1 binding sites we the model in which A1 bound to and CE4 with one to and repress the 5′ splice site in a manner that is similar to the of sequences M. Chabot B. EMBO J. 1999; 18: PubMed Scopus (158) Google Scholar). The of elements and of A1/A2 binding sites be similar to a of sequences that the of and the has In the presence of multiple A1 binding sites, the and CE4 therefore be and the complex be A in be obtained by which have been in the of a of A1 bound to sequences J. L. Krainer A.R. Genes Dev. 1999; 13: PubMed Scopus Google Scholar). of binding sites is a that is in elements splice site selection. In binding sites contribute to the assembly of a enhancer complex Cell. Full Text PDF PubMed Scopus Google Scholar, Genes Dev. PubMed Scopus Google Scholar, M. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). has been that this the of sequence the enhancer and the 3′ splice site B.R. K.J. EMBO J. 1998; 17: PubMed Scopus Google Scholar). The introns upstream and downstream of the alternative exon in the fibroblast growth factor receptor and also binding sites for the hnRNP tract-binding protein (reviewed in Ref. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar). of the that have been to hnRNP A/B proteins are with the presence of high affinity binding sites. In addition to a role in the selection of 5′ splice sites, many have implicated A/B binding sites in the control of 3′ splice site M. A. Krainer A.R. Zahler A.M. EMBO J. 1999; 18: PubMed Scopus Google Scholar, A. Krainer A.R. J. 2001; PubMed Scopus Google Scholar, S. J. J. EMBO J. 2001; 20: PubMed Scopus Google Scholar, M. S. H. P. H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H. H. P. EMBO J. 1998; 17: PubMed Scopus Google Scholar). the for this has not been in all cases, a that an high affinity A1 binding site can with the binding of some SR proteins to a exon splicing enhancer J. A. Krainer A.R. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In this case, the of A1 with the element with the binding of A1 J. A. Krainer A.R. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the mechanisms by which and A1 binding sites splice site selection be different, are mediated by the binding of multiple A1 and for the of nuclear for and members of the Chabot for for the

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