CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair
Abstract To tolerate oxidative stress, cells enable DNA repair responses often sensitive to poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibition—an intervention effective against cancers lacking BRCA1/2. Here, we demonstrate that mutating the CHD6 chromatin remodeler sensitizes cells to PA...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56085-5 |
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| author | Luc Provencher Wilson Nartey Peter M. Brownlee Austin W. Atkins Jean-Philippe Gagné Lou Baudrier Nicholas S. Y. Ting Cortt G. Piett Shujuan Fang Dustin D. Pearson Shaun Moore Pierre Billon Zachary D. Nagel Guy G. Poirier Gareth J. Williams Aaron A. Goodarzi |
| author_facet | Luc Provencher Wilson Nartey Peter M. Brownlee Austin W. Atkins Jean-Philippe Gagné Lou Baudrier Nicholas S. Y. Ting Cortt G. Piett Shujuan Fang Dustin D. Pearson Shaun Moore Pierre Billon Zachary D. Nagel Guy G. Poirier Gareth J. Williams Aaron A. Goodarzi |
| author_sort | Luc Provencher |
| collection | DOAJ |
| description | Abstract To tolerate oxidative stress, cells enable DNA repair responses often sensitive to poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibition—an intervention effective against cancers lacking BRCA1/2. Here, we demonstrate that mutating the CHD6 chromatin remodeler sensitizes cells to PARP1/2 inhibitors in a manner distinct from BRCA1, and that CHD6 recruitment to DNA damage requires cooperation between PAR- and DNA-binding domains essential for nucleosome sliding activity. CHD6 displays direct PAR-binding, interacts with PARP-1 and other PAR-associated proteins, and combined DNA- and PAR-binding loss eliminates CHD6 relocalization to DNA damage. While CHD6 loss does not impair RAD51 foci formation or DNA double-strand break repair, it causes sensitivity to replication stress, and PARP1/2-trapping or Pol ζ inhibitor-induced γH2AX foci accumulation in S-phase. DNA repair pathway screening reveals that CHD6 loss elicits insufficiency in apurinic-apyrimidinic endonuclease (APEX1) activity and genomic abasic site accumulation. We reveal APEX1-linked roles for CHD6 important for understanding PARP1/2-trapping inhibitor sensitivity. |
| format | Article |
| id | doaj-art-7fd1f7c36e624311aa0755cce48291b5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7fd1f7c36e624311aa0755cce48291b52025-01-26T12:42:28ZengNature PortfolioNature Communications2041-17232025-01-0116112410.1038/s41467-025-56085-5CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repairLuc Provencher0Wilson Nartey1Peter M. Brownlee2Austin W. Atkins3Jean-Philippe Gagné4Lou Baudrier5Nicholas S. Y. Ting6Cortt G. Piett7Shujuan Fang8Dustin D. Pearson9Shaun Moore10Pierre Billon11Zachary D. Nagel12Guy G. Poirier13Gareth J. Williams14Aaron A. Goodarzi15Robson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryDepartment of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research CenterRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryHarvard University, School of Public HealthRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryHarvard University, School of Public HealthDepartment of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research CenterRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryRobson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of CalgaryAbstract To tolerate oxidative stress, cells enable DNA repair responses often sensitive to poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibition—an intervention effective against cancers lacking BRCA1/2. Here, we demonstrate that mutating the CHD6 chromatin remodeler sensitizes cells to PARP1/2 inhibitors in a manner distinct from BRCA1, and that CHD6 recruitment to DNA damage requires cooperation between PAR- and DNA-binding domains essential for nucleosome sliding activity. CHD6 displays direct PAR-binding, interacts with PARP-1 and other PAR-associated proteins, and combined DNA- and PAR-binding loss eliminates CHD6 relocalization to DNA damage. While CHD6 loss does not impair RAD51 foci formation or DNA double-strand break repair, it causes sensitivity to replication stress, and PARP1/2-trapping or Pol ζ inhibitor-induced γH2AX foci accumulation in S-phase. DNA repair pathway screening reveals that CHD6 loss elicits insufficiency in apurinic-apyrimidinic endonuclease (APEX1) activity and genomic abasic site accumulation. We reveal APEX1-linked roles for CHD6 important for understanding PARP1/2-trapping inhibitor sensitivity.https://doi.org/10.1038/s41467-025-56085-5 |
| spellingShingle | Luc Provencher Wilson Nartey Peter M. Brownlee Austin W. Atkins Jean-Philippe Gagné Lou Baudrier Nicholas S. Y. Ting Cortt G. Piett Shujuan Fang Dustin D. Pearson Shaun Moore Pierre Billon Zachary D. Nagel Guy G. Poirier Gareth J. Williams Aaron A. Goodarzi CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair Nature Communications |
| title | CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair |
| title_full | CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair |
| title_fullStr | CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair |
| title_full_unstemmed | CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair |
| title_short | CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair |
| title_sort | chd6 has poly adp ribose and dna binding domains and regulates parp1 2 trapping inhibitor sensitivity via abasic site repair |
| url | https://doi.org/10.1038/s41467-025-56085-5 |
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