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Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency

TP53 deficiency in cancer is associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Using live cell imaging of DNA double-strand breaks (DSBs) and cell cycle state tra...

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Autores principales: Kumar, Rashmi J, Chao, Hui Xiao, Simpson, Dennis A, Feng, Wanjuan, Cho, Min-Guk, Roberts, Victoria R, Sullivan, Aurora R, Shah, Sonam J, Wozny, Anne-Sophie, Fagan-Solis, Katerina, Kumar, Sunil, Luthman, Adam, Ramsden, Dale A, Purvis, Jeremy E, Gupta, Gaorav P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751686/
https://www.ncbi.nlm.nih.gov/pubmed/33385162
http://dx.doi.org/10.1093/narcan/zcaa038
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author Kumar, Rashmi J
Chao, Hui Xiao
Simpson, Dennis A
Feng, Wanjuan
Cho, Min-Guk
Roberts, Victoria R
Sullivan, Aurora R
Shah, Sonam J
Wozny, Anne-Sophie
Fagan-Solis, Katerina
Kumar, Sunil
Luthman, Adam
Ramsden, Dale A
Purvis, Jeremy E
Gupta, Gaorav P
author_facet Kumar, Rashmi J
Chao, Hui Xiao
Simpson, Dennis A
Feng, Wanjuan
Cho, Min-Guk
Roberts, Victoria R
Sullivan, Aurora R
Shah, Sonam J
Wozny, Anne-Sophie
Fagan-Solis, Katerina
Kumar, Sunil
Luthman, Adam
Ramsden, Dale A
Purvis, Jeremy E
Gupta, Gaorav P
author_sort Kumar, Rashmi J
collection PubMed
description TP53 deficiency in cancer is associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Using live cell imaging of DNA double-strand breaks (DSBs) and cell cycle state transitions, we show that p53-deficient cells exhibit accelerated repair of radiomimetic-induced DSBs arising in S phase. Low-dose DNA-dependent protein kinase (DNA-PK) inhibition increases the S-phase DSB burden in p53-deficient cells, resulting in elevated rates of mitotic catastrophe. However, a subset of p53-deficient cells exhibits intrinsic resistance to radiomimetic-induced DSBs despite DNA-PK inhibition. We show that p53-deficient cells under DNA-PK inhibition utilize DNA polymerase theta (Pol θ)-mediated end joining repair to promote their viability in response to therapy-induced DSBs. Pol θ inhibition selectively increases S-phase DSB burden after radiomimetic therapy and promotes prolonged G2 arrest. Dual inhibition of DNA-PK and Pol θ restores radiation sensitivity in p53-deficient cells as well as in p53-mutant breast cancer cell lines. Thus, combination targeting of DNA-PK- and Pol θ-dependent end joining repair represents a promising strategy for overcoming resistance to DNA damaging therapies in p53-deficient cancers.
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spelling pubmed-77516862020-12-29 Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency Kumar, Rashmi J Chao, Hui Xiao Simpson, Dennis A Feng, Wanjuan Cho, Min-Guk Roberts, Victoria R Sullivan, Aurora R Shah, Sonam J Wozny, Anne-Sophie Fagan-Solis, Katerina Kumar, Sunil Luthman, Adam Ramsden, Dale A Purvis, Jeremy E Gupta, Gaorav P NAR Cancer DNA Damage Sensing and Repair TP53 deficiency in cancer is associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Using live cell imaging of DNA double-strand breaks (DSBs) and cell cycle state transitions, we show that p53-deficient cells exhibit accelerated repair of radiomimetic-induced DSBs arising in S phase. Low-dose DNA-dependent protein kinase (DNA-PK) inhibition increases the S-phase DSB burden in p53-deficient cells, resulting in elevated rates of mitotic catastrophe. However, a subset of p53-deficient cells exhibits intrinsic resistance to radiomimetic-induced DSBs despite DNA-PK inhibition. We show that p53-deficient cells under DNA-PK inhibition utilize DNA polymerase theta (Pol θ)-mediated end joining repair to promote their viability in response to therapy-induced DSBs. Pol θ inhibition selectively increases S-phase DSB burden after radiomimetic therapy and promotes prolonged G2 arrest. Dual inhibition of DNA-PK and Pol θ restores radiation sensitivity in p53-deficient cells as well as in p53-mutant breast cancer cell lines. Thus, combination targeting of DNA-PK- and Pol θ-dependent end joining repair represents a promising strategy for overcoming resistance to DNA damaging therapies in p53-deficient cancers. Oxford University Press 2020-12-21 /pmc/articles/PMC7751686/ /pubmed/33385162 http://dx.doi.org/10.1093/narcan/zcaa038 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle DNA Damage Sensing and Repair
Kumar, Rashmi J
Chao, Hui Xiao
Simpson, Dennis A
Feng, Wanjuan
Cho, Min-Guk
Roberts, Victoria R
Sullivan, Aurora R
Shah, Sonam J
Wozny, Anne-Sophie
Fagan-Solis, Katerina
Kumar, Sunil
Luthman, Adam
Ramsden, Dale A
Purvis, Jeremy E
Gupta, Gaorav P
Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency
title Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency
title_full Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency
title_fullStr Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency
title_full_unstemmed Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency
title_short Dual inhibition of DNA-PK and DNA polymerase theta overcomes radiation resistance induced by p53 deficiency
title_sort dual inhibition of dna-pk and dna polymerase theta overcomes radiation resistance induced by p53 deficiency
topic DNA Damage Sensing and Repair
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751686/
https://www.ncbi.nlm.nih.gov/pubmed/33385162
http://dx.doi.org/10.1093/narcan/zcaa038
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