C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption
Abstract While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40779-9 |
| _version_ | 1797414704381952000 |
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| author | Abhishek Bharadwaj Sharma Muhammad Khairul Ramlee Joel Kosmin Martin R. Higgs Amy Wolstenholme George E. Ronson Dylan Jones Daniel Ebner Noor Shamkhi David Sims Paul W. G. Wijnhoven Josep V. Forment Ian Gibbs-Seymour Nicholas D. Lakin |
| author_facet | Abhishek Bharadwaj Sharma Muhammad Khairul Ramlee Joel Kosmin Martin R. Higgs Amy Wolstenholme George E. Ronson Dylan Jones Daniel Ebner Noor Shamkhi David Sims Paul W. G. Wijnhoven Josep V. Forment Ian Gibbs-Seymour Nicholas D. Lakin |
| author_sort | Abhishek Bharadwaj Sharma |
| collection | DOAJ |
| description | Abstract While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors. |
| first_indexed | 2024-03-09T05:37:25Z |
| format | Article |
| id | doaj.art-173fc00005584212ac6ca37aec8c9ac4 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:37:25Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-173fc00005584212ac6ca37aec8c9ac42023-12-03T12:27:25ZengNature PortfolioNature Communications2041-17232023-08-0114111510.1038/s41467-023-40779-9C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruptionAbhishek Bharadwaj Sharma0Muhammad Khairul Ramlee1Joel Kosmin2Martin R. Higgs3Amy Wolstenholme4George E. Ronson5Dylan Jones6Daniel Ebner7Noor Shamkhi8David Sims9Paul W. G. Wijnhoven10Josep V. Forment11Ian Gibbs-Seymour12Nicholas D. Lakin13Department of Biochemistry, University of OxfordDepartment of Biochemistry, University of OxfordDepartment of Biochemistry, University of OxfordInstitute of Cancer and Genomic Sciences, University of BirminghamDepartment of Biochemistry, University of OxfordDepartment of Biochemistry, University of OxfordTarget Discovery Institute, Nuffield Department of Medicine, University of OxfordTarget Discovery Institute, Nuffield Department of Medicine, University of OxfordDepartment of Biochemistry, University of OxfordWeatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe HospitalEarly Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical CampusEarly Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical CampusDepartment of Biochemistry, University of OxfordDepartment of Biochemistry, University of OxfordAbstract While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors.https://doi.org/10.1038/s41467-023-40779-9 |
| spellingShingle | Abhishek Bharadwaj Sharma Muhammad Khairul Ramlee Joel Kosmin Martin R. Higgs Amy Wolstenholme George E. Ronson Dylan Jones Daniel Ebner Noor Shamkhi David Sims Paul W. G. Wijnhoven Josep V. Forment Ian Gibbs-Seymour Nicholas D. Lakin C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption Nature Communications |
| title | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_full | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_fullStr | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_full_unstemmed | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_short | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_sort | c16orf72 hapstr1 tapr1 functions with brca1 senataxin to modulate replication associated r loops and confer resistance to parp disruption |
| url | https://doi.org/10.1038/s41467-023-40779-9 |
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