CUGBP1

CELF1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CPZ, 2DHS, 2RQ4, 2RQC, 3NMR, 3NNA, 3NNC, 3NNH
Identifiers
Aliases	CELF1, BRUNOL2, CUG-BP, CUGBP, CUGBP1, EDEN-BP, NAB50, NAPOR, hNab50, CUGBP, Elav-like family member 1, CUGBP Elav-like family member 1
External IDs	OMIM: 601074; MGI: 1342295; HomoloGene: 136342; GeneCards: CELF1; OMA:CELF1 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p11.2 Start 47,465,933 bp[1] End 47,565,569 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte tail of epididymis caput epididymis corpus epididymis renal medulla trabecular bone pylorus seminal vesicula mucosa of paranasal sinus bronchial epithelial cell n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function translation repressor activity, mRNA regulatory element binding protein binding RNA binding nucleic acid binding BRE binding mRNA binding pre-mRNA binding Cellular component cytoplasm membrane nucleoplasm nucleus ribonucleoprotein complex Biological process germ cell development embryo development mRNA processing RNA interference regulation of RNA splicing RNA splicing negative regulation of translation mRNA splice site selection regulation of alternative mRNA splicing, via spliceosome embryo development ending in birth or egg hatching Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10658 13046 Ensembl ENSG00000149187 ENSMUSG00000005506 UniProt Q92879 P28659 RefSeq (mRNA) NM_001025596 NM_001172639 NM_001172640 NM_006560 NM_198700 NM_001330272 NM_001244891 NM_001244903 NM_017368 NM_198683 RefSeq (protein) NP_001020767 NP_001166110 NP_001166111 NP_001317201 NP_006551 NP_941989 NP_001363298 NP_001363299 NP_001363300 NP_001363301 NP_001363302 NP_001363303 NP_001363305 NP_001363306 NP_001363307 NP_001363308 NP_001363309 NP_001363310 NP_001363311 NP_001363312 NP_001363313 NP_001363314 NP_001363315 NP_001363316 NP_001363317 NP_001363318 NP_001363319 NP_001363320 NP_001363322 NP_001363324 NP_001363325 NP_001363326 NP_001363328 NP_001363335 NP_001363336 NP_001363337 NP_001363338 NP_001363339 NP_001363340 NP_001363341 NP_001363342 NP_001363343 NP_001363344 NP_001363346 NP_001363347 NP_001363348 NP_001363349 NP_001363350 NP_001363351 NP_001363352 NP_001363353 NP_001363354 NP_001363355 NP_001363356 NP_001363357 NP_001363358 NP_001363359 NP_001363360 NP_001363361 NP_001363362 NP_001363363 NP_001363364 NP_001363365 NP_001363366 NP_001363367 NP_001363368 NP_001363369 NP_001363370 NP_001363371 NP_001363372 NP_001363373 NP_001363374 NP_001363375 NP_001363376 NP_001363377 NP_001363378 NP_001363379 NP_001363380 NP_001363381 NP_001363382 NP_001363383 NP_001363384 NP_001363385 NP_001363386 NP_001363387 NP_001363388 NP_001363389 NP_001363390 NP_001363391 NP_001363392 NP_001363304 NP_001231820 NP_001231832 NP_059064 NP_941955 NP_001393093 NP_001393094 NP_001393095 NP_001393096 NP_001393097 NP_001393098 NP_001393099 NP_001393100 NP_001393101 NP_001393102 NP_001393103 NP_001393104 NP_001393105 NP_001393106 NP_001393107 NP_001393108 NP_001393109 NP_001393110 NP_001393111 NP_001393112 NP_001393113 Location (UCSC) Chr 11: 47.47 – 47.57 Mb n/a PubMed search [2] [3]
Wikidata
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CUG triplet repeat, RNA binding protein 1, also known as CUGBP1, is a protein which in humans is encoded by the CUGBP1 gene.^[4][5][6]

Function

Members of the CELF/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.^[4]

mRNA degradation factor

It is estimated that 5 to 8% of human mRNAs are unstable because of mRNA instability elements in their 3' untranslated regions (3'UTR).^[7] 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.^[8]

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^[9] 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.^[10]

Human CUGBP1 (hCUGBP1) had been previously identified by Timchenko and colleagues^[5] 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.^[11] 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.^[12] In rescue experiments in xenopus egg extracts, the recombinant human protein can replace the xenopus one making them functional homolog.^[13] Furthermore, the Poly(A) ribonuclease PARN was shown to interact with CUGBP1.^[14] In human cells, tethering of hCUGBP1 to a mRNA decreases its steadystate suggesting the destabilization of the mRNA.^[15] 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.^[16] Both xCUGBP1 and hCUGBP1 were shown to specifically bind to c-jun ARE.^[12] 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.^[17]

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.^[18] More recently, the reappraisal 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.^[19] Such a motif is found in a number of unstable mRNAs in human cells^[17] suggesting that they are degraded by a CUGBP1 deadenylation dependent pathway.

References

External links

• Human CELF1 genome location and CELF1 gene details page in the UCSC Genome Browser.

Further reading