DNA-PK promotes DNA end resection at DNA double strand breaks in G0 cells
- Weill Cornell Medicine, United States
- University of Alabama at Birmingham, United States
- National Cancer Institute, United States
Abstract
DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs are predominately repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 murine and human cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G1 or G2 phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, which has important implications for DNA DSB repair in quiescent cells.
Data availability
Sequencing data have been deposited in GEO under accession codesGSE186087
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DNA-PK Promotes DNA End Resection at DNA Double Strand Breaks in G0 cellsNCBI Gene Expression Omnibus, GSE186087.
Article and author information
Author details
Funding
NIH Office of the Director (R35 GM139816)
- Jessica K Tyler
NIH Office of the Director (RO1 CA95641)
- Jessica K Tyler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Wolf-Dietrich Heyer, University of California, Davis, United States
Publication history
- Received: October 14, 2021
- Preprint posted: October 21, 2021 (view preprint)
- Accepted: May 6, 2022
- Accepted Manuscript published: May 16, 2022 (version 1)
- Version of Record published: May 20, 2022 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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DNA-PK promotes DNA end resection at DNA double strand breaks in G0 cells
eLife 11:e74700.
https://doi.org/10.7554/eLife.74700
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