Dynamic basis for dGâ¢dT misincorporation via tautomerization and ionization.
Nature
; 554(7691): 195-201, 2018 02 08.
Article
en En
| MEDLINE
| ID: mdl-29420478
ABSTRACT
Tautomeric and anionic Watson-Crick-like mismatches have important roles in replication and translation errors through mechanisms that are not fully understood. Here, using NMR relaxation dispersion, we resolve a sequence-dependent kinetic network connecting Gâ¢T/U wobbles with three distinct Watson-Crick mismatches two rapidly exchanging tautomeric species (Genolâ¢T/UGâ¢Tenol/Uenol; population less than 0.4%) and one anionic species (Gâ¢T-/U-; population around 0.001% at neutral pH). The sequence-dependent tautomerization or ionization step was inserted into a minimal kinetic mechanism for correct incorporation during replication after the initial binding of the nucleotide, leading to accurate predictions of the probability of dGâ¢dT misincorporation across different polymerases and pH conditions and for a chemically modified nucleotide, and providing mechanisms for sequence-dependent misincorporation. Our results indicate that the energetic penalty for tautomerization and/or ionization accounts for an approximately 10-2 to 10-3-fold discrimination against misincorporation, which proceeds primarily via tautomeric dGenolâ¢dT and dGâ¢dTenol, with contributions from anionic dGâ¢dT- dominant at pH 8.4 and above or for some mutagenic nucleotides.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Timina
/
ADN
/
Mutagénesis
/
Disparidad de Par Base
/
ADN Polimerasa Dirigida por ADN
/
Replicación del ADN
/
Guanina
Límite:
Animals
/
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article