CUGBP1
Encyclopedia
CUG triplet repeat, RNA binding protein 1, also known as CUGBP1, is a protein
which in humans is encoded by the CUGBP1 gene
.
/BRUNOL protein family contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing, and translation. This gene may play a role in myotonic dystrophy type 1 (DM1) via interactions with the dystrophia myotonica-protein kinase (DMPK
) gene. Alternative splicing
results in multiple transcript variants encoding different isoforms
.
are unstable because of mRNA instability elements in their 3' untranslated regions (3'UTR
). A number of such elements have been called AU-rich elements (AREs
). It is now known that AREs are binding sites for RNA-binding proteins that target mRNAs to rapid degradation. However, only few of the proteins reported to bind AREs were demonstrated to play a role in mRNA degradation. A shared feature of these proteins is to bind only to a subclass of the known AREs that contain the pentamer AUUUA. A convergent effort of several research teams now adds CUGBP1 (CUG binding protein 1) to the short list of ARE-Binding proteins that control mRNA stability, with the peculiarity that it binds to non-AUUUA AREs. CUGBP1 has been involved both as a key regulator of human myotonic dystrophy 1 (DM1) and more recently as a regulator of human papilloma virus mRNA expression.
Evidence for CUGBP1 acting as a RNA degradation factor came first from the Xenopus
model. Xenopus CUGBP1 (xCUGBP1, formerly known as EDEN-BP) was identified in 1998 for its ability to bind specifically to a GU-rich element (Embryonic deadenylation element EDEN) located in the 3'UTRs of some mRNAs that are rapidly deadenylated and translationally repressed after fertilization in early development. Because deadenylation is often the rate limiting step of mRNA degradation the enhancement of deadenylation increases mRNA turnover.
Human CUGBP1 (hCUGBP1) had been previously identified by Timchenko and colleagues for its ability to bind to CUG repeats located in the DMPK 3'UTR. A large amount of work has since described the role of hCUGBP1 on control of alternative splicing and will not be discussed here. The demonstration that hCUGBP1 is involved in the control of mRNA deadenylation and instability like xCUGBP1 came next. In mammalian cell extract as well as in xenopus egg extracts, depletion and rescue experiments showed that specific binding of CUGBP1 to the 3'UTR of mRNA is required for the targeted specific deadenylation to occur. In rescue experiments in xenopus egg extracts, the recombinant human protein can replace the xenopus one making them functional homolog. Furthermore, the Poly(A) ribonuclease PARN was shown to interact with CUGBP1. In human cells, tethering of hCUGBP1 to a mRNA decreases its steadystate suggesting the destabilization of the mRNA. The first human mRNA reported to be targeted to rapid deadenylation and degradation by CUGBP1 is the oncogene c-jun. Years ago, it was shown that the class III ARE (devoid of any AUUUA motif) of the human c-jun oncogene directed rapid deadenylation and degradation to a reporter mRNA. Both xCUGBP1 and hCUGBP1 were shown to specifically bind to c-jun ARE. The binding of CUGBP1 to the 3'UTR of mRNAs bearing GU-rich element would target these mRNAs for rapid deadenylation by PARN and subsequent degradation. This was recently demonstrated by siRNA-mediated knockdown of hCUGBP1 that led to stabilization of a reporter RNA bearing the c-jun UG -rich ARE.
UGU(G/A) tetranucleotides are key determinants of the binding site for xCUGBP1. A SELEX
approach for the identification of artificial substrate of hCUGBP1 led to the proposition that UGU containing sequences were highly favoured for binding. More recently, the reappraisial of CUGBP1 binding sites on the base of a combination of the SELEX approach and
Immunoprecipitation
of the CUGBP1 containing complexes has led Graindorge et al. to propose a 15 nt motif as a key determinant of CUGBP1 binding. Interestingly, such a motif is found in a number of unstable mRNAs in human cells suggesting that they are degraded by a CUGBP1 deadenylation dependant pathway.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the CUGBP1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
Members of the CELFCEBPD
CCAAT/enhancer-binding protein delta is a protein that in humans is encoded by the CEBPD gene.-Interactions:CEBPD has been shown to interact with Mothers against decapentaplegic homolog 3.- External links :...
/BRUNOL protein family contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing, and translation. This gene may play a role in myotonic dystrophy type 1 (DM1) via interactions with the dystrophia myotonica-protein kinase (DMPK
Myotonic dystrophy protein kinase
Myotonin-protein kinase also known as myotonic dystrophy protein kinase or dystrophia myotonica protein kinase is an enzyme that in humans is encoded by the DMPK gene.- Function :...
) gene. Alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
results in multiple transcript variants encoding different isoforms
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
.
mRNA degradation factor
It is estimated that 5 to 8 % of human mRNAsMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
are unstable because of mRNA instability elements in their 3' untranslated regions (3'UTR
Three prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
). A number of such elements have been called AU-rich elements (AREs
AU-rich element
AU-rich elements are one of the most common types of regulatory elements found in mRNAs. They are involved in the control of gene expression. They are the most common determinant of RNA stability in mammalian cells....
). It is now known that AREs are binding sites for RNA-binding proteins that target mRNAs to rapid degradation. However, only few of the proteins reported to bind AREs were demonstrated to play a role in mRNA degradation. A shared feature of these proteins is to bind only to a subclass of the known AREs that contain the pentamer AUUUA. A convergent effort of several research teams now adds CUGBP1 (CUG binding protein 1) to the short list of ARE-Binding proteins that control mRNA stability, with the peculiarity that it binds to non-AUUUA AREs. CUGBP1 has been involved both as a key regulator of human myotonic dystrophy 1 (DM1) and more recently as a regulator of human papilloma virus mRNA expression.
Evidence for CUGBP1 acting as a RNA degradation factor came first from the Xenopus
Xenopus
Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
model. Xenopus CUGBP1 (xCUGBP1, formerly known as EDEN-BP) was identified in 1998 for its ability to bind specifically to a GU-rich element (Embryonic deadenylation element EDEN) located in the 3'UTRs of some mRNAs that are rapidly deadenylated and translationally repressed after fertilization in early development. Because deadenylation is often the rate limiting step of mRNA degradation the enhancement of deadenylation increases mRNA turnover.
Human CUGBP1 (hCUGBP1) had been previously identified by Timchenko and colleagues for its ability to bind to CUG repeats located in the DMPK 3'UTR. A large amount of work has since described the role of hCUGBP1 on control of alternative splicing and will not be discussed here. The demonstration that hCUGBP1 is involved in the control of mRNA deadenylation and instability like xCUGBP1 came next. In mammalian cell extract as well as in xenopus egg extracts, depletion and rescue experiments showed that specific binding of CUGBP1 to the 3'UTR of mRNA is required for the targeted specific deadenylation to occur. In rescue experiments in xenopus egg extracts, the recombinant human protein can replace the xenopus one making them functional homolog. Furthermore, the Poly(A) ribonuclease PARN was shown to interact with CUGBP1. In human cells, tethering of hCUGBP1 to a mRNA decreases its steadystate suggesting the destabilization of the mRNA. The first human mRNA reported to be targeted to rapid deadenylation and degradation by CUGBP1 is the oncogene c-jun. Years ago, it was shown that the class III ARE (devoid of any AUUUA motif) of the human c-jun oncogene directed rapid deadenylation and degradation to a reporter mRNA. Both xCUGBP1 and hCUGBP1 were shown to specifically bind to c-jun ARE. The binding of CUGBP1 to the 3'UTR of mRNAs bearing GU-rich element would target these mRNAs for rapid deadenylation by PARN and subsequent degradation. This was recently demonstrated by siRNA-mediated knockdown of hCUGBP1 that led to stabilization of a reporter RNA bearing the c-jun UG -rich ARE.
UGU(G/A) tetranucleotides are key determinants of the binding site for xCUGBP1. A SELEX
Systematic Evolution of Ligands by Exponential Enrichment
SELEX , also referred to as in vitro selection or in vitro evolution, is a combinatorial chemistry technique in molecular biology for producing oligonucleotides of either single-stranded DNA or RNA that specifically bind to a target ligand or ligands....
approach for the identification of artificial substrate of hCUGBP1 led to the proposition that UGU containing sequences were highly favoured for binding. More recently, the reappraisial of CUGBP1 binding sites on the base of a combination of the SELEX approach and
Immunoprecipitation
Immunoprecipitation
Immunoprecipitation is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins...
of the CUGBP1 containing complexes has led Graindorge et al. to propose a 15 nt motif as a key determinant of CUGBP1 binding. Interestingly, such a motif is found in a number of unstable mRNAs in human cells suggesting that they are degraded by a CUGBP1 deadenylation dependant pathway.