Polµ tumor variants decrease the efficiency and accuracy of NHEJ.
Nucleic Acids Res
; 45(17): 10018-10031, 2017 Sep 29.
Article
em En
| MEDLINE
| ID: mdl-28973441
ABSTRACT
The non homologous end-joining (NHEJ) pathway of double-strand break (DSB) repair often requires DNA synthesis to fill the gaps generated upon alignment of the broken ends, a complex task performed in human cells by two specialized DNA polymerases, Polλ and Polµ. It is now well established that Polµ is the one adapted to repair DSBs with non-complementary ends, the most challenging scenario, although the structural basis and physiological implications of this adaptation are not fully understood. Here, we demonstrate that two human Polµ point mutations, G174S and R175H, previously identified in two different tumor samples and affecting two adjacent residues, limit the efficiency of accurate NHEJ by Polµ in vitro and in vivo. Moreover, we show that this limitation is the consequence of a decreased template dependency during NHEJ, which renders the error-rate of the mutants higher due to the ability of Polµ to randomly incorporate nucleotides at DSBs. These results highlight the relevance of the 8 kDa domain of Polµ for accurate and efficient NHEJ, but also its contribution to the error-prone behavior of Polµ at 2-nt gaps. This work provides the first demonstration that mutations affecting Polµ identified in tumors can alter the efficiency and fidelity of NHEJ.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mutagênese
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Mutação Puntual
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Mutação de Sentido Incorreto
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DNA Polimerase Dirigida por DNA
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Reparo do DNA por Junção de Extremidades
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article