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ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells

The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these se...

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Autores principales: Verma, Priyanka, Zhou, Yeqiao, Cao, Zhendong, Deraska, Peter V., Deb, Moniher, Arai, Eri, Li, Weihua, Shao, Yue, Puentes, Laura, Li, Yiwen, Patankar, Sonali, Mach, Robert H., Faryabi, Robert B., Shi, Junwei, Greenberg, Roger A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880902/
https://www.ncbi.nlm.nih.gov/pubmed/33462394
http://dx.doi.org/10.1038/s41556-020-00624-3
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author Verma, Priyanka
Zhou, Yeqiao
Cao, Zhendong
Deraska, Peter V.
Deb, Moniher
Arai, Eri
Li, Weihua
Shao, Yue
Puentes, Laura
Li, Yiwen
Patankar, Sonali
Mach, Robert H.
Faryabi, Robert B.
Shi, Junwei
Greenberg, Roger A.
author_facet Verma, Priyanka
Zhou, Yeqiao
Cao, Zhendong
Deraska, Peter V.
Deb, Moniher
Arai, Eri
Li, Weihua
Shao, Yue
Puentes, Laura
Li, Yiwen
Patankar, Sonali
Mach, Robert H.
Faryabi, Robert B.
Shi, Junwei
Greenberg, Roger A.
author_sort Verma, Priyanka
collection PubMed
description The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identify the PAR-binding chromatin remodeler, ALC1/CHD1L, as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication associated DNA damage, increased PARP trapping, and a reliance on HR. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.
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spelling pubmed-78809022021-07-18 ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells Verma, Priyanka Zhou, Yeqiao Cao, Zhendong Deraska, Peter V. Deb, Moniher Arai, Eri Li, Weihua Shao, Yue Puentes, Laura Li, Yiwen Patankar, Sonali Mach, Robert H. Faryabi, Robert B. Shi, Junwei Greenberg, Roger A. Nat Cell Biol Article The response to Poly (ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identify the PAR-binding chromatin remodeler, ALC1/CHD1L, as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of BRCA-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication associated DNA damage, increased PARP trapping, and a reliance on HR. These findings establish PAR-dependent chromatin remodeling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers. 2021-01-18 2021-02 /pmc/articles/PMC7880902/ /pubmed/33462394 http://dx.doi.org/10.1038/s41556-020-00624-3 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Verma, Priyanka
Zhou, Yeqiao
Cao, Zhendong
Deraska, Peter V.
Deb, Moniher
Arai, Eri
Li, Weihua
Shao, Yue
Puentes, Laura
Li, Yiwen
Patankar, Sonali
Mach, Robert H.
Faryabi, Robert B.
Shi, Junwei
Greenberg, Roger A.
ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
title ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
title_full ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
title_fullStr ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
title_full_unstemmed ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
title_short ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells
title_sort alc1 links chromatin accessibility to parp inhibitor response in homologous recombination-deficient cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880902/
https://www.ncbi.nlm.nih.gov/pubmed/33462394
http://dx.doi.org/10.1038/s41556-020-00624-3
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