Dimers of DNA-PK create a stage for DNA double-strand break repair.
Nat Struct Mol Biol
; 28(1): 13-19, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-33077952
ABSTRACT
DNA double-strand breaks are the most dangerous type of DNA damage and, if not repaired correctly, can lead to cancer. In humans, Ku70/80 recognizes DNA broken ends and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form DNA-dependent protein kinase holoenzyme (DNA-PK) in the process of non-homologous end joining (NHEJ). We present a 2.8-Å-resolution cryo-EM structure of DNA-PKcs, allowing precise amino acid sequence registration in regions uninterpreted in previous 4.3-Å X-ray maps. We also report a cryo-EM structure of DNA-PK at 3.5-Å resolution and reveal a dimer mediated by the Ku80 C terminus. Central to dimer formation is a domain swap of the conserved C-terminal helix of Ku80. Our results suggest a new mechanism for NHEJ utilizing a DNA-PK dimer to bring broken DNA ends together. Furthermore, drug inhibition of NHEJ in combination with chemo- and radiotherapy has proved successful, making these models central to structure-based drug targeting efforts.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
DNA
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Proteína Quinase Ativada por DNA
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Quebras de DNA de Cadeia Dupla
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Reparo do DNA por Junção de Extremidades
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Autoantígeno Ku
Limite:
Humans
Idioma:
En
Revista:
Nat Struct Mol Biol
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Reino Unido