Identification of the main barriers to Ku accumulation in chromatin.
Cell Rep
; 43(8): 114538, 2024 Aug 27.
Article
em En
| MEDLINE
| ID: mdl-39058590
ABSTRACT
Repair of DNA double-strand breaks by the non-homologous end-joining pathway is initiated by the binding of Ku to DNA ends. Multiple Ku proteins load onto linear DNAs in vitro. However, in cells, Ku loading is limited to â¼1-2 molecules per DNA end. The mechanisms enforcing this limit are currently unclear. Here, we show that the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), but not its protein kinase activity, is required to prevent excessive Ku entry into chromatin. Ku accumulation is further restricted by two mechanisms a neddylation/FBXL12-dependent process that actively removes loaded Ku molecules throughout the cell cycle and a CtIP/ATM-dependent mechanism that operates in S phase. Finally, we demonstrate that the misregulation of Ku loading leads to impaired transcription in the vicinity of DNA ends. Together, our data shed light on the multiple mechanisms operating to prevent Ku from invading chromatin and interfering with other DNA transactions.
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Base de dados:
MEDLINE
Assunto principal:
Cromatina
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Proteína Quinase Ativada por DNA
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Autoantígeno Ku
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article