The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase ß.
Nucleic Acids Res
; 42(17): 11233-45, 2014.
Article
em En
| MEDLINE
| ID: mdl-25200079
ABSTRACT
To provide molecular-level insights into the spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase ß (polß), we report four crystal structures of polß complexed with dGâ¢dTTP and dAâ¢dCTP mismatches in the presence of Mg2+ or Mn2+. The Mg(2+)-bound ground-state structures show that the dAâ¢dCTP-Mg2+ complex adopts an 'intermediate' protein conformation while the dGâ¢dTTP-Mg2+ complex adopts an open protein conformation. The Mn(2+)-bound 'pre-chemistry-state' structures show that the dAâ¢dCTP-Mn2+ complex is structurally very similar to the dAâ¢dCTP-Mg2+ complex, whereas the dGâ¢dTTP-Mn2+ complex undergoes a large-scale conformational change to adopt a Watson-Crick-like dGâ¢dTTP base pair and a closed protein conformation. These structural differences, together with our molecular dynamics simulation studies, suggest that polß increases replication fidelity via a two-stage mismatch discrimination mechanism, where one is in the ground state and the other in the closed conformation state. In the closed conformation state, polß appears to allow only a Watson-Crick-like conformation for purineâ¢pyrimidine base pairs, thereby discriminating the mismatched base pairs based on their ability to form the Watson-Crick-like conformation. Overall, the present studies provide new insights into the spontaneous replication error and the replication fidelity mechanisms of polß.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
DNA Polimerase beta
/
Pareamento Incorreto de Bases
/
Replicação do DNA
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article