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Short-range end resection requires ATAD5-mediated PCNA unloading for faithful homologous recombination

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Title
Short-range end resection requires ATAD5-mediated PCNA unloading for faithful homologous recombination
Author(s)
Su Hyung Park; Namwoo Kim; Nalae Kang; Eunjin Ryu; Eun A. Lee; Jae Sun Ra; Anton Gartner; Sukhyun Kang; Kyungjae Myung; Kyoo-young Lee
Publication Date
2023-10
Journal
NUCLEIC ACIDS RESEARCH, v.51, no.19, pp.10519 - 10535
Publisher
OXFORD UNIV PRESS
Abstract
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. Graphical Abstract
URI
https://pr.ibs.re.kr/handle/8788114/14309
DOI
10.1093/nar/gkad776
ISSN
0305-1048
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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