A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy.
DBR1
RNA lariat
RNA processing
spliceosome
transcription
trichothiodystrophy
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
06 07 2023
06 07 2023
Historique:
received:
20
06
2022
revised:
25
03
2023
accepted:
06
06
2023
pmc-release:
06
07
2024
medline:
10
7
2023
pubmed:
28
6
2023
entrez:
27
6
2023
Statut:
ppublish
Résumé
The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.
Identifiants
pubmed: 37369199
pii: S1097-2765(23)00433-1
doi: 10.1016/j.molcel.2023.06.011
pmc: PMC10483886
mid: NIHMS1912454
pii:
doi:
Substances chimiques
lariat debranching enzyme
EC 2.7.7.-
RNA Nucleotidyltransferases
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2258-2275.e11Subventions
Organisme : NCI NIH HHS
ID : R35 CA220430
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM105681
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA254143
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193318
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM127472
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227001
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA092584
Pays : United States
Organisme : Wellcome Trust
ID : 220300Z/20/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Am J Hum Genet. 2019 Mar 7;104(3):520-529
pubmed: 30824121
Hum Mol Genet. 2021 Aug 28;30(18):1711-1720
pubmed: 33909043
Sci Rep. 2019 Feb 26;9(1):2779
pubmed: 30808927
J Cell Biol. 2013 Nov 11;203(3):457-70
pubmed: 24217620
Am J Med Genet A. 2020 Mar;182(3):513-520
pubmed: 31880405
Genes Dev. 1999 May 15;13(10):1234-9
pubmed: 10346811
Methods Mol Biol. 2014;1126:83-96
pubmed: 24549657
Cell. 1984 Aug;38(1):317-31
pubmed: 6088074
Nucleic Acids Res. 2015 Sep 3;43(15):e97
pubmed: 25925576
Science. 2021 Jan 15;371(6526):305-309
pubmed: 33446560
Crit Rev Biochem Mol Biol. 2016 Sep;51(5):395-411
pubmed: 27622638
Mol Cell. 2011 Nov 4;44(3):373-84
pubmed: 22055184
Mol Cell. 1999 Mar;3(3):405-11
pubmed: 10198643
Bioinformatics. 2012 Aug 15;28(16):2184-5
pubmed: 22743226
PLoS Genet. 2016 Nov 21;12(11):e1006422
pubmed: 27870853
Oncogene. 2017 Sep 21;36(38):5382-5391
pubmed: 28504715
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14727-14732
pubmed: 27930312
Cell Rep. 2020 Nov 24;33(8):108416
pubmed: 33238114
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Hum Mol Genet. 2017 Dec 1;26(23):4689-4698
pubmed: 28973399
Mol Cell. 2021 Oct 21;81(20):4228-4242.e8
pubmed: 34686315
Nature. 1998 Sep 3;395(6697):93-6
pubmed: 9738505
Mol Cell. 2006 Sep 1;23(5):673-84
pubmed: 16949364
Nat Protoc. 2016 Aug;11(8):1455-76
pubmed: 27442863
Mol Cell. 2018 Apr 19;70(2):265-273.e8
pubmed: 29656923
Mol Cell. 2021 Mar 4;81(5):998-1012.e7
pubmed: 33440169
Nat Rev Genet. 2019 Dec;20(12):705-723
pubmed: 31399713
Am J Hum Genet. 2005 Mar;76(3):510-6
pubmed: 15645389
Mol Cell. 2014 May 22;54(4):683-90
pubmed: 24793692
Genes Dev. 2014 Dec 1;28(23):2663-76
pubmed: 25452276
Mol Cell. 2014 Mar 6;53(5):779-90
pubmed: 24560925
Cell. 2018 Jan 25;172(3):454-464.e11
pubmed: 29361316
Nature. 2007 Jul 5;448(7149):83-6
pubmed: 17589500
Nat Struct Mol Biol. 2008 Aug;15(8):819-26
pubmed: 18641664
Cell. 2009 Jul 23;138(2):389-403
pubmed: 19615732
Cell. 1991 May 3;65(3):483-92
pubmed: 1850323
Mol Cell. 2003 Jul;12(1):113-23
pubmed: 12887897
Nat Struct Mol Biol. 2016 Sep 6;23(9):771-7
pubmed: 27605205
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Science. 2020 Feb 7;367(6478):694-699
pubmed: 32029630
Nucleic Acids Res. 2014;42(16):10845-55
pubmed: 25123664
Nature. 2014 Sep 4;513(7516):120-3
pubmed: 25141179
J Med Genet. 2015 Apr;52(4):269-74
pubmed: 25612912
BMC Bioinformatics. 2009 May 27;10:161
pubmed: 19473525
J Med Genet. 2008 Oct;45(10):609-21
pubmed: 18603627
Cell. 2017 Feb 23;168(5):843-855.e13
pubmed: 28215706
Mol Cell Biol. 1997 Feb;17(2):809-18
pubmed: 9001235
Nat Rev Mol Cell Biol. 2017 Apr;18(4):263-273
pubmed: 28248323
Cell. 2011 Jan 7;144(1):16-26
pubmed: 21215366
Methods Enzymol. 2017;592:1-26
pubmed: 28668116
Cell. 2009 Feb 20;136(4):701-18
pubmed: 19239890
J Invest Dermatol. 2015 Mar;135(3):734-741
pubmed: 25290684
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Am J Med Genet A. 2020 Mar;182(3):565-569
pubmed: 31793730
Int J Mol Sci. 2015 Feb 09;16(2):3705-21
pubmed: 25671812
Cell. 2007 Jul 13;130(1):89-100
pubmed: 17599402
Cold Spring Harb Perspect Biol. 2019 Aug 1;11(8):
pubmed: 31371351
Nature. 1985 Feb 14-20;313(6003):552-7
pubmed: 2578627
Genome Res. 2019 Oct;29(10):1591-1604
pubmed: 31434678
PLoS Biol. 2019 Aug 23;17(8):e3000423
pubmed: 31442222
Cell Rep. 2018 Nov 6;25(6):1404-1414.e6
pubmed: 30403997
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nature. 2016 Sep 15;537(7620):427-431
pubmed: 27556946
Mol Genet Genomics. 2011 Dec;286(5-6):395-410
pubmed: 22065066
J Biol Chem. 2018 Aug 31;293(35):13524-13533
pubmed: 29997253
Mol Cell. 2018 Feb 1;69(3):505-516.e5
pubmed: 29395066
Nat Commun. 2020 Mar 9;11(1):1270
pubmed: 32152280
Annu Rev Pharmacol Toxicol. 2016;56:427-45
pubmed: 26514200
Nature. 2001 Feb 15;409(6822):860-921
pubmed: 11237011
Nature. 2004 Oct 21;431(7011):931-45
pubmed: 15496913
Nature. 2017 Nov 16;551(7680):389-393
pubmed: 29144457
Nat Struct Mol Biol. 2015 Feb;22(2):138-44
pubmed: 25599396
Genes Dev. 2018 Apr 1;32(7-8):577-591
pubmed: 29666160
Am J Hum Genet. 2016 Apr 7;98(4):627-42
pubmed: 26996949
Cell. 2018 Feb 22;172(5):952-965.e18
pubmed: 29474921
Am J Hum Genet. 2019 Aug 1;105(2):434-440
pubmed: 31374204
FEBS Lett. 1995 Oct 23;374(1):130-4
pubmed: 7589500
Cell. 2009 May 15;137(4):708-20
pubmed: 19450518
Annu Rev Biochem. 2015;84:165-98
pubmed: 26034889
Nat Methods. 2017 Apr;14(4):417-419
pubmed: 28263959
Mol Cell. 1998 Jun;1(7):981-90
pubmed: 9651581
Trends Ecol Evol. 2022 Apr;37(4):299-308
pubmed: 34920907
Hum Mutat. 2007 Jan;28(1):92-6
pubmed: 16977596
EMBO J. 2013 Aug 14;32(16):2264-74
pubmed: 23892457
Mol Cell. 2021 May 6;81(9):1920-1934.e9
pubmed: 33689748
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5593-601
pubmed: 25480548
Cell Mol Life Sci. 2007 Mar;64(5):632-40
pubmed: 17310276
Nucleic Acids Res. 2009 Feb;37(3):891-902
pubmed: 19103666
Mol Biol Cell. 2013 Nov;24(22):3557-68
pubmed: 24048450
In Silico Biol. 2005;5(4):347-65
pubmed: 16268780