Short-range end resection requires ATAD5-mediated PCNA unloading for faithful homologous recombination.
Nucleic Acids Res
; 51(19): 10519-10535, 2023 10 27.
Article
in En
| MEDLINE
| ID: mdl-37739427
Homologous recombination (HR) requires bidirectional end resection initiated by a nick formed close to a DNA double-strand break (DSB), dysregulation favoring error-prone DNA end-joining pathways. Here we investigate the role of the ATAD5, a PCNA unloading protein, in short-range end resection, long-range resection not being affected by ATAD5 deficiency. Rapid PCNA loading onto DNA at DSB sites depends on the RFC PCNA loader complex and MRE11-RAD50-NBS1 nuclease complexes bound to CtIP. Based on our cytological analyses and on an in vitro system for short-range end resection, we propose that PCNA unloading by ATAD5 is required for the completion of short-range resection. Hampering PCNA unloading also leads to failure to remove the KU70/80 complex from the termini of DSBs hindering DNA repair synthesis and the completion of HR. In line with this model, ATAD5-depleted cells are defective for HR, show increased sensitivity to camptothecin, a drug forming protein-DNA adducts, and an augmented dependency on end-joining pathways. Our study highlights the importance of PCNA regulation at DSB for proper end resection and HR.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Repair
/
DNA Breaks, Double-Stranded
Limits:
Humans
Language:
En
Journal:
Nucleic Acids Res
Year:
2023
Document type:
Article
Country of publication:
United kingdom