Frustration Between Preferred States of Complementary Trinucleotide Repeat DNA Hairpins Anticorrelates with Expansion Disease Propensity.
Huntington's disease
hairpin slippage
kinetics
molecular dynamics
single molecule FRET
trinucleotide interrupts
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
15 05 2023
15 05 2023
Historique:
received:
14
11
2022
revised:
21
03
2023
accepted:
30
03
2023
pmc-release:
15
05
2024
medline:
1
5
2023
pubmed:
7
4
2023
entrez:
6
4
2023
Statut:
ppublish
Résumé
DNA trinucleotide repeat (TRs) expansion beyond a threshold often results in human neurodegenerative diseases. The mechanisms causing expansions remain unknown, although the tendency of TR ssDNA to self-associate into hairpins that slip along their length is widely presumed related. Here we apply single molecule FRET (smFRET) experiments and molecular dynamics simulations to determine conformational stabilities and slipping dynamics for CAG, CTG, GAC and GTC hairpins. Tetraloops are favored in CAG (89%), CTG (89%) and GTC (69%) while GAC favors triloops. We also determined that TTG interrupts near the loop in the CTG hairpin stabilize the hairpin against slipping. The different loop stabilities have implications for intermediate structures that may form when TR-containing duplex DNA opens. Opposing hairpins in the (CAG) ∙ (CTG) duplex would have matched stability whereas opposing hairpins in a (GAC) ∙ (GTC) duplex would have unmatched stability, introducing frustration in the (GAC) ∙ (GTC) opposing hairpins that could encourage their resolution to duplex DNA more rapidly than in (CAG) ∙ (CTG) structures. Given that the CAG and CTG TR can undergo large, disease-related expansion whereas the GAC and GTC sequences do not, these stability differences can inform and constrain models of expansion mechanisms of TR regions.
Identifiants
pubmed: 37024008
pii: S0022-2836(23)00148-1
doi: 10.1016/j.jmb.2023.168086
pmc: PMC10191799
mid: NIHMS1892265
pii:
doi:
Substances chimiques
DNA
9007-49-2
DNA, Complementary
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
168086Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM118508
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Références
Biochemistry. 2012 Jan 10;51(1):52-62
pubmed: 22148399
Nucleic Acids Res. 1995 Jul 25;23(14):2706-14
pubmed: 7651831
J Phys Chem B. 2009 May 14;113(19):6881-93
pubmed: 19374420
Nucleic Acids Res. 2020 Mar 18;48(5):2232-2245
pubmed: 31974547
Nat Methods. 2018 Sep;15(9):669-676
pubmed: 30171252
Angew Chem Int Ed Engl. 2013 Aug 12;52(33):8566-9
pubmed: 23794476
J Phys Chem B. 2013 Dec 19;117(50):16105-9
pubmed: 24261629
Nat Rev Genet. 2010 Nov;11(11):786-99
pubmed: 20953213
Cell. 1995 May 19;81(4):533-40
pubmed: 7758107
Comput Struct Biotechnol J. 2021 Apr 26;19:2819-2832
pubmed: 34093995
Biochemistry. 2011 May 31;50(21):4441-50
pubmed: 21526744
Genetics. 1995 Nov;141(3):825-32
pubmed: 8582629
Nucleic Acids Res. 2022 May 20;50(9):4860-4876
pubmed: 35536254
Biochemistry. 2010 Apr 13;49(14):3174-90
pubmed: 20180598
ACS Chem Neurosci. 2018 May 16;9(5):1104-1117
pubmed: 29281254
Nature. 2007 Jun 21;447(7147):932-40
pubmed: 17581576
Nat Methods. 2016 Apr;13(4):341-4
pubmed: 26878382
Biophys J. 2010 Aug 4;99(3):961-70
pubmed: 20682275
Nucleic Acids Res. 2005 Mar 14;33(5):1604-17
pubmed: 15767285
J Mol Biol. 2003 May 30;329(2):351-61
pubmed: 12758081
Hum Mol Genet. 1999 Jan;8(1):123-8
pubmed: 9887340
J Biol Chem. 2020 Mar 27;295(13):4134-4170
pubmed: 32060097
Nat Rev Genet. 2005 Oct;6(10):729-42
pubmed: 16205713
Nucleic Acids Res. 2005 Jul 21;33(13):4065-77
pubmed: 16040598
Crit Rev Biochem Mol Biol. 2015 Mar-Apr;50(2):142-67
pubmed: 25608779
Nat Rev Mol Cell Biol. 2010 Mar;11(3):165-70
pubmed: 20177394
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4950-4
pubmed: 8197163
Lancet Neurol. 2017 Jan;16(1):88-96
pubmed: 27979358
Cells. 2021 Apr 26;10(5):
pubmed: 33925919
Curr Opin Struct Biol. 2006 Jun;16(3):351-8
pubmed: 16713248
Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9535-9540
pubmed: 28827328
J Neurosci Methods. 1991 Nov;40(1):71-86
pubmed: 1795554
J Phys Chem B. 2018 Apr 26;122(16):4491-4512
pubmed: 29617130
Molecules. 2014 Sep 03;19(9):13735-54
pubmed: 25255759
Nucleic Acids Res. 2018 Jan 25;46(2):942-955
pubmed: 29190385
Nucleic Acids Res. 2020 Sep 25;48(17):9899-9917
pubmed: 32821947
DNA Repair (Amst). 2008 Jul 1;7(7):1121-34
pubmed: 18472310
Biochemistry. 1996 Apr 16;35(15):5041-53
pubmed: 8664297
Nat Methods. 2016 Jan;13(1):55-8
pubmed: 26569599
J Phys Chem B. 2013 Oct 10;117(40):11932-42
pubmed: 24041226
J Am Chem Soc. 2012 Apr 4;134(13):6033-44
pubmed: 22397401
Annu Rev Neurosci. 2000;23:217-47
pubmed: 10845064
Methods Enzymol. 2016;581:285-315
pubmed: 27793283
DNA Repair (Amst). 2016 Feb;38:117-126
pubmed: 26774442
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3535-3542
pubmed: 32015124
J Biol Chem. 1998 Feb 27;273(9):5204-10
pubmed: 9478975
Cell. 2019 Aug 8;178(4):887-900.e14
pubmed: 31398342
Am J Hum Genet. 2019 Jun 6;104(6):1116-1126
pubmed: 31104771
Annu Rev Biochem. 2015;84:199-226
pubmed: 25580529
Nat Commun. 2022 Sep 14;13(1):5402
pubmed: 36104339
Biophys J. 2017 Jul 11;113(1):19-36
pubmed: 28700917
ACS Chem Neurosci. 2017 Mar 15;8(3):578-591
pubmed: 27933757
J Phys Chem Lett. 2019 Jul 18;10(14):3985-3990
pubmed: 31241956
Nat Rev Genet. 2004 Jun;5(6):435-45
pubmed: 15153996
Bio Protoc. 2021 Sep 20;11(18):e4155
pubmed: 34692905
J Mol Biol. 1998 Jan 9;275(1):3-16
pubmed: 9451434
J Biol Chem. 2000 Jun 16;275(24):18382-90
pubmed: 10849445
Biochemistry. 1993 Jan 19;32(2):436-54
pubmed: 8422353
Neuron. 2022 Apr 6;110(7):1173-1192.e7
pubmed: 35114102
Nat Commun. 2021 Jan 8;12(1):204
pubmed: 33420051
Eur Biophys J. 2001 Jul;30(3):179-85
pubmed: 11508837
J Biol Chem. 1996 Jan 26;271(4):1853-6
pubmed: 8567629
ACS Omega. 2022 Oct 24;7(43):38728-38743
pubmed: 36340174
PLoS One. 2011 Mar 29;6(3):e17951
pubmed: 21479228
J Huntingtons Dis. 2021;10(1):75-94
pubmed: 33579865