MBNL1 explained

Muscleblind Like Splicing Regulator 1 (MBNL1) is an RNA splicing protein that in humans is encoded by the MBNL1 gene.^{[1] [2] [3]} It has a well characterized role in Myotonic dystrophy where impaired splicing disrupts muscle development and function.^[4] In addition to regulating mRNA maturation of hundreds of genes MBNL1 (along with its paralogs MBNL2 & MBNL3) autoregulate alternative splicing of the MBNL1 pre-mRNA transcript.^[5] The founding member of the human MBNL family of proteins was the Drosophila Muscleblind protein (PMID 9334280).

Human MBNL1 is an alternative splicing regulator that harbors dual function as both a repressor and activator for terminal muscle differentiation.^[6] The repressive function of Human MBNL1 by sequestering at normal splice sites has been shown to lead to RNA-splicing defects that lead to muscular diseases.^[7] The gene can be alternatively spliced into multiple functionally distinct isoforms, some of which linked to be involved in cancer biology.^[8]

Human MBNL1 is a 370 amino acid protein^[9] composed of four Zinc Finger protein domains of the CCCH type linked in tandem. The MBNL1 protein specifically binds to double stranded CUG RNA expansions.^[10] The Zinc Finger domains play a role in both protein:protein contacts as well as RNA:protein contacts when bound to an oligonucleotide.

Further reading

• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Fardaei M, Larkin K, Brook JD, Hamshere MG . In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts . Nucleic Acids Research . 29 . 13 . 2766–71 . July 2001 . 11433021 . 55763 . 10.1093/nar/29.13.2766 .
• Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, Henderson D, Schalling M, Swanson MS, Thornton CA . 6 . Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2 . Human Molecular Genetics . 10 . 19 . 2165–70 . September 2001 . 11590133 . 10.1093/hmg/10.19.2165 . free .
• Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, Brook JD . Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells . Human Molecular Genetics . 11 . 7 . 805–14 . April 2002 . 11929853 . 10.1093/hmg/11.7.805 . free .
• Kino Y, Mori D, Oma Y, Takeshita Y, Sasagawa N, Ishiura S . Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats . Human Molecular Genetics . 13 . 5 . 495–507 . March 2004 . 14722159 . 10.1093/hmg/ddh056 . 10.1.1.598.7921 .
• Dansithong W, Paul S, Comai L, Reddy S . MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1 . The Journal of Biological Chemistry . 280 . 7 . 5773–80 . February 2005 . 15546872 . 10.1074/jbc.M410781200 . free .
• Ho TH, Savkur RS, Poulos MG, Mancini MA, Swanson MS, Cooper TA . Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy . Journal of Cell Science . 118 . Pt 13 . 2923–33 . July 2005 . 15961406 . 10.1242/jcs.02404 . free .
• Adereth Y, Dammai V, Kose N, Li R, Hsu T . RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1 . Nature Cell Biology . 7 . 12 . 1240–7 . December 2005 . 16273094 . 2365307 . 10.1038/ncb1335 .
• Monferrer L, Artero R . An interspecific functional complementation test in Drosophila for introductory genetics laboratory courses . The Journal of Heredity . 97 . 1 . 67–73 . 2006 . 16394256 . 10.1093/jhered/esj003 . free .
• Cardani R, Mancinelli E, Rotondo G, Sansone V, Meola G . Muscleblind-like protein 1 nuclear sequestration is a molecular pathology marker of DM1 and DM2 . European Journal of Histochemistry . 50 . 3 . 177–82 . 2007 . 16920640 .
• Paul S, Dansithong W, Kim D, Rossi J, Webster NJ, Comai L, Reddy S . Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing . The EMBO Journal . 25 . 18 . 4271–83 . September 2006 . 16946708 . 1570429 . 10.1038/sj.emboj.7601296 . 10.1.1.673.6397 .
• Smith KP, Byron M, Johnson C, Xing Y, Lawrence JB . Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains . The Journal of Cell Biology . 178 . 6 . 951–64 . September 2007 . 17846170 . 2064620 . 10.1083/jcb.200706048 .

Notes and References

1. Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 4 . 5 . 307–13 . October 1997 . 9455477 . 10.1093/dnares/4.5.307 . free .
2. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS . Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy . The EMBO Journal . 19 . 17 . 4439–48 . September 2000 . 10970838 . 302046 . 10.1093/emboj/19.17.4439 .
3. Web site: Entrez Gene: MBNL1 muscleblind-like (Drosophila).
4. Ho TH, Charlet-B N, Poulos MG, Singh G, Swanson MS, Cooper TA . Muscleblind proteins regulate alternative splicing . The EMBO Journal . 23 . 15 . 3103–12 . August 2004 . 15257297 . 514918 . 10.1038/sj.emboj.7600300 .
5. Konieczny P, Stepniak-Konieczna E, Sobczak K . MBNL expression in autoregulatory feedback loops . RNA Biology . 15 . 1 . 1–8 . January 2018 . 28949831 . 5786016 . 10.1080/15476286.2017.1384119 .
6. Teplova M, Patel DJ . Structural insights into RNA recognition by the alternative-splicing regulator muscleblind-like MBNL1 . Nature Structural & Molecular Biology . 15 . 12 . 1343–51 . December 2008 . 19043415 . 4689322 . 10.1038/nsmb.1519 .
7. Yadava RS, Kim YK, Mandal M, Mahadevan K, Gladman JT, Yu Q, Mahadevan MS . MBNL1 overexpression is not sufficient to rescue the phenotypes in a mouse model of RNA toxicity . Human Molecular Genetics . 28 . 14 . 2330–2338 . July 2019 . 30997488 . 6606845 . 10.1093/hmg/ddz065 .
8. Tabaglio . Tommaso . Low . Diana HP . Teo . Winnie Koon Lay . Goy . Pierre Alexis . Cywoniuk . Piotr . Wollmann . Heike . Ho . Jessica . Tan . Damien . Aw . Joey . Pavesi . Andrea . Sobczak . Krzysztof . Wee . Dave Keng Boon . Guccione . Ernesto . October 2018 . MBNL1 alternative splicing isoforms play opposing roles in cancer . Life Science Alliance . en . 1 . 5 . e201800157 . 10.26508/lsa.201800157 . 2575-1077 . 6238595 . 30456384.
9. Biophysical characterization of the 117 amino acids long N-terminal segment of D-Raf (Isoform A). 10.31274/rtd-180813-16211. Iowa State University. Oren. Tchaicheeyan . 2007. vanc . free.
10. Web site: MBNL1 muscleblind like splicing regulator 1 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2019-05-05.