A fidelity mechanism in DNA polymerase lambda promotes error-free bypass of 8-oxo-dG.
EMBO J
; 35(18): 2045-59, 2016 09 15.
Article
em En
| MEDLINE
| ID: mdl-27481934
ABSTRACT
8-oxo-7,8-dihydroxy-2'-deoxyguanosine (8-oxo-dG) has high mutagenic potential as it is prone to mispair with deoxyadenine (dA). In order to maintain genomic integrity, post-replicative 8-oxo-dGdA mispairs are removed through DNA polymerase lambda (Pol λ)-dependent MUTYH-initiated base excision repair (BER). Here, we describe seven novel crystal structures and kinetic data that fully characterize 8-oxo-dG bypass by Pol λ. We demonstrate that Pol λ has a flexible active site that can tolerate 8-oxo-dG in either the anti- or syn-conformation. Importantly, we show that discrimination against the pro-mutagenic syn-conformation occurs at the extension step and identify the residue responsible for this selectivity. This residue acts as a kinetic switch, shunting repair toward long-patch BER upon correct dCMP incorporation, thus enhancing repair efficiency. Moreover, this switch also provides a potential mechanism to increase repair fidelity of MUTYH-initiated BER.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Polimerase beta
/
Pareamento Incorreto de Bases
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Desoxiguanosina
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Reparo do DNA
Limite:
Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2016
Tipo de documento:
Article