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DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells

DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G(2) phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G(1) phase and non-cycling quiescent (G(0)) cells where DSBs are predominately repaired by non-homologous end joining (NHEJ)....

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Autores principales: Fowler, Faith C, Chen, Bo-Ruei, Zolnerowich, Nicholas, Wu, Wei, Pavani, Raphael, Paiano, Jacob, Peart, Chelsea, Chen, Zulong, Nussenzweig, André, Sleckman, Barry P, Tyler, Jessica K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122494/
https://www.ncbi.nlm.nih.gov/pubmed/35575473
http://dx.doi.org/10.7554/eLife.74700
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author Fowler, Faith C
Chen, Bo-Ruei
Zolnerowich, Nicholas
Wu, Wei
Pavani, Raphael
Paiano, Jacob
Peart, Chelsea
Chen, Zulong
Nussenzweig, André
Sleckman, Barry P
Tyler, Jessica K
author_facet Fowler, Faith C
Chen, Bo-Ruei
Zolnerowich, Nicholas
Wu, Wei
Pavani, Raphael
Paiano, Jacob
Peart, Chelsea
Chen, Zulong
Nussenzweig, André
Sleckman, Barry P
Tyler, Jessica K
author_sort Fowler, Faith C
collection PubMed
description DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G(2) phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G(1) phase and non-cycling quiescent (G(0)) 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 G(0) 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 G(0) 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 G(0) cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G(1) or G(2) phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G(0), but not in G(1) or G(2) phase cells, which has important implications for DNA DSB repair in quiescent cells.
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spelling pubmed-91224942022-05-21 DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells Fowler, Faith C Chen, Bo-Ruei Zolnerowich, Nicholas Wu, Wei Pavani, Raphael Paiano, Jacob Peart, Chelsea Chen, Zulong Nussenzweig, André Sleckman, Barry P Tyler, Jessica K eLife Chromosomes and Gene Expression DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G(2) phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G(1) phase and non-cycling quiescent (G(0)) 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 G(0) 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 G(0) 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 G(0) cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in proliferating cells at the G(1) or G(2) phase of the cell cycle was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G(0), but not in G(1) or G(2) phase cells, which has important implications for DNA DSB repair in quiescent cells. eLife Sciences Publications, Ltd 2022-05-16 /pmc/articles/PMC9122494/ /pubmed/35575473 http://dx.doi.org/10.7554/eLife.74700 Text en https://creativecommons.org/publicdomain/zero/1.0/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 (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Chromosomes and Gene Expression
Fowler, Faith C
Chen, Bo-Ruei
Zolnerowich, Nicholas
Wu, Wei
Pavani, Raphael
Paiano, Jacob
Peart, Chelsea
Chen, Zulong
Nussenzweig, André
Sleckman, Barry P
Tyler, Jessica K
DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells
title DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells
title_full DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells
title_fullStr DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells
title_full_unstemmed DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells
title_short DNA-PK promotes DNA end resection at DNA double strand breaks in G(0) cells
title_sort dna-pk promotes dna end resection at dna double strand breaks in g(0) cells
topic Chromosomes and Gene Expression
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122494/
https://www.ncbi.nlm.nih.gov/pubmed/35575473
http://dx.doi.org/10.7554/eLife.74700
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