Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/150608
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dc.contributor.authorTan, Jiazien_US
dc.contributor.authorYang, Lixiaen_US
dc.contributor.authorOng, Alan Ann Lerken_US
dc.contributor.authorShi, Jiahaoen_US
dc.contributor.authorZhong, Zhenshengen_US
dc.contributor.authorLye, Mun Lengen_US
dc.contributor.authorLiu, Shiyien_US
dc.contributor.authorLisowiec-Wachnicka, Jolantaen_US
dc.contributor.authorKierzek, Ryszarden_US
dc.contributor.authorRoca, Xavieren_US
dc.contributor.authorChen, Gangen_US
dc.date.accessioned2021-06-01T06:23:37Z-
dc.date.available2021-06-01T06:23:37Z-
dc.date.issued2019-
dc.identifier.citationTan, J., Yang, L., Ong, A. A. L., Shi, J., Zhong, Z., Lye, M. L., Liu, S., Lisowiec-Wachnicka, J., Kierzek, R., Roca, X. & Chen, G. (2019). A disease-causing intronic point mutation C19G alters tau exon 10 splicing via RNA secondary structure rearrangement. Biochemistry, 58(12), 1565-1578. https://dx.doi.org/10.1021/acs.biochem.9b00001en_US
dc.identifier.issn0006-2960en_US
dc.identifier.other0000-0002-8772-9755-
dc.identifier.urihttps://hdl.handle.net/10356/150608-
dc.description.abstractAlternative splicing of MAPT cassette exon 10 produces tau isoforms with four microtubule-binding repeat domains (4R) upon exon inclusion or three repeats (3R) upon exon skipping. In human neurons, deviations from the ∼1:1 physiological 4R:3R ratio lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Certain FTDP-17-associated mutations affect a regulatory hairpin that sequesters the exon 10 5′ splice site (5′ss, located at the exon 10–intron 10 junction). These mutations tend to increase the 4R:3R ratio by destabilizing the hairpin, thereby improving 5′ss recognition by U1 snRNP. Interestingly, a single C-to-G mutation at the 19th nucleotide in intron 10 (C19G or +19G) decreases the level of exon 10 inclusion significantly from 56% to 1%, despite the disruption of a G-C base pair in the bottom stem of the hairpin. Here, we show by biophysical characterization, including thermal melting, fluorescence, and single-molecule mechanical unfolding using optical tweezers, that the +19G mutation alters the structure of the bottom stem, resulting in the formation of a new bottom stem with enhanced stability. The cell culture alternative splicing patterns of a series of minigenes reveal that the splicing activities of the mutants with destabilizing mutations on the top stem can be compensated in a position-dependent manner by the +19G mutation in the bottom stem. We observed an excellent correlation between the level of exon 10 inclusion and the rate of mechanical unfolding at 10 pN, indicating that the unfolding of the splice site hairpins (to facilitate subsequent binding of U1 snRNA) may be aided by helicases or other proteins.en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.language.isoenen_US
dc.relationRG42/15en_US
dc.relationRG152/17en_US
dc.relationRG33/15en_US
dc.relationMOE2015-T2-1-028en_US
dc.relation.ispartofBiochemistryen_US
dc.rights© 2019 American Chemical Society. All rights reserved.en_US
dc.subjectScience::Chemistryen_US
dc.titleA disease-causing intronic point mutation C19G alters tau exon 10 splicing via RNA secondary structure rearrangementen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Physical and Mathematical Sciencesen_US
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.identifier.doi10.1021/acs.biochem.9b00001-
dc.identifier.pmid30793898-
dc.identifier.scopus2-s2.0-85063478082-
dc.identifier.issue12en_US
dc.identifier.volume58en_US
dc.identifier.spage1565en_US
dc.identifier.epage1578en_US
dc.subject.keywordsFree Energyen_US
dc.subject.keywordsMeltingen_US
dc.description.acknowledgementThis work was supported by grants from Singapore Ministry of Education (MOE) Tier 1 (RG42/15 and RG152/17 to G.C. and RG33/15 to X.R.) and MOE Tier 2 (MOE2015-T2-1-028 to G.C.). This work was also supported by the National Science Center (UMO-2013/08/A/ST5/00295 to R.K. and UMO-2016/21/D/NZ5/01906 to J.L.-W.) and the Polish Ministry of Science and Higher Education under the KNOW program.en_US
item.grantfulltextnone-
item.fulltextNo Fulltext-
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