HnRNP G and Tra2β:: opposite effects on splicing matched by antagonism in RNA binding

被引:84
作者
Nasim, MT [1 ]
Chernova, TK [1 ]
Chowdhury, HM [1 ]
Yue, BG [1 ]
Eperon, IC [1 ]
机构
[1] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England
基金
英国惠康基金;
关键词
D O I
10.1093/hmg/ddg136
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The hnRNP G family comprises three closely related proteins, hnRNP G, RBMY and hnRNP G-T. We showed previously that they interact with splicing activator proteins, particularly hTra2beta, and suggested that they were involved in regulating Tra2-dependent splicing. We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor. HnRNP G acts via a specific sequence to repress the skeletal muscle-specific exon (SK) of human slow skeletal alpha-tropomyosin, TPM3, and stimulates inclusion of the alternative non-muscle exon. The binding of hnRNP G to the exon is antagonized by hTra2beta. The two proteins also have opposite effects upon a dystrophin pseudo-exon. This exon is incorporated in a patient to a higher level in heart muscle than skeletal muscle, causing X-linked dilated cardiomyopathy. It is included to a higher level after transfection of a mini-gene into rodent cardiac myoblasts than into skeletal muscle myoblasts. Co-transfection with hnRNP G represses incorporation in cardiac myoblasts, whereas hTra2beta increases it in skeletal myoblasts. Both the cell specificity and the protein responses depend upon exon sequences. Since the ratio of hnRNP G to Tra2beta mRNA in humans is higher in skeletal muscle than in heart muscle, we propose that the hnRNP G/Tra2beta ratio contributes to the cellular splicing preferences and that the higher proportion of hnRNP G in skeletal muscle plays a role in preventing the incorporation of the pseudo-exon and thus in preventing skeletal muscle dystrophy.
引用
收藏
页码:1337 / 1348
页数:12
相关论文
共 43 条
[31]   RBMY evolved on the Y chromosome from a ubiquitously transcribed X-Y identical gene [J].
Mazeyrat, S ;
Saut, N ;
Mattei, MG ;
Mitchell, MJ .
NATURE GENETICS, 1999, 22 (03) :224-226
[32]   A double reporter assay for detecting changes in the ratio of spliced and unspliced mRNA in mammalian cells [J].
Nasim, MT ;
Chowdhury, HM ;
Eperon, IC .
NUCLEIC ACIDS RESEARCH, 2002, 30 (20) :e109
[33]   Human transformer-2-beta gene (SFRS10): Complete nucleotide sequence, chromosomal localization, and generation of a tissue-specific isoform [J].
Nayler, O ;
Cap, C ;
Stamm, S .
GENOMICS, 1998, 53 (02) :191-202
[34]   A NOVEL 43-KDA GLYCOPROTEIN IS DETECTED IN THE NUCLEUS OF MAMMALIAN-CELLS BY AUTOANTIBODIES FROM DOGS WITH AUTOIMMUNE DISORDERS [J].
SOULARD, M ;
BARQUE, JP ;
DELLAVALLE, V ;
HERNANDEZVERDUN, D ;
MASSON, C ;
DANON, F ;
LARSEN, CJ .
EXPERIMENTAL CELL RESEARCH, 1991, 193 (01) :59-71
[35]   HNRNP-G - SEQUENCE AND CHARACTERIZATION OF A GLYCOSYLATED RNA-BINDING PROTEIN [J].
SOULARD, M ;
DELLAVALLE, V ;
SIOMI, MC ;
PINOLROMA, S ;
CODOGNO, P ;
BAUVY, C ;
BELLINI, M ;
LACROIX, JC ;
MONOD, G ;
DREYFUSS, G ;
LARSEN, CJ .
NUCLEIC ACIDS RESEARCH, 1993, 21 (18) :4210-4217
[36]   Regulation of the neuron-specific exon of clathrin light chain B [J].
Stamm, S ;
Casper, D ;
Hanson, V ;
Helfman, DM .
MOLECULAR BRAIN RESEARCH, 1999, 64 (01) :108-118
[37]   Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing [J].
Tacke, R ;
Tohyama, M ;
Ogawa, S ;
Manley, JL .
CELL, 1998, 93 (01) :139-148
[38]   A SPLICING ENHANCER COMPLEX CONTROLS ALTERNATIVE SPLICING OF DOUBLESEX PREMESSENGER RNA [J].
TIAN, M ;
MANIATIS, T .
CELL, 1993, 74 (01) :105-114
[39]   RBMY, a probable human spermatogenesis factor, and other hnRNP G proteins interact with Tra2β and affect splicing [J].
Venables, JP ;
Elliott, DJ ;
Makarova, OV ;
Makarov, EM ;
Cooke, HJ ;
Eperon, IC .
HUMAN MOLECULAR GENETICS, 2000, 9 (05) :685-694
[40]   T-STAR/ETOILE: a novel relative of SAM68 that interacts with an RNA-binding protein implicated in spermatogenesis [J].
Venables, JP ;
Vernet, C ;
Chew, L ;
Elliott, DJ ;
Cowmeadow, RB ;
Wu, J ;
Cooke, HJ ;
Artzt, K ;
Eperon, IC .
HUMAN MOLECULAR GENETICS, 1999, 8 (06) :959-969