A consensus set of genetic vulnerabilities to ATR inhibition
The response to DNA replication stress in eukaryotes is under the control of the ataxia–telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomple...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Royal Society
2019-09-01
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| Series: | Open Biology |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.190156 |
| _version_ | 1818299272847687680 |
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| author | Nicole Hustedt Alejandro Álvarez-Quilón Andrea McEwan Jing Yi Yuan Tiffany Cho Lisa Koob Traver Hart Daniel Durocher |
| author_facet | Nicole Hustedt Alejandro Álvarez-Quilón Andrea McEwan Jing Yi Yuan Tiffany Cho Lisa Koob Traver Hart Daniel Durocher |
| author_sort | Nicole Hustedt |
| collection | DOAJ |
| description | The response to DNA replication stress in eukaryotes is under the control of the ataxia–telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase ε accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity and the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic. |
| first_indexed | 2024-12-13T04:48:36Z |
| format | Article |
| id | doaj.art-de50d630a77649aab35abfdcf2bf902d |
| institution | Directory Open Access Journal |
| issn | 2046-2441 |
| language | English |
| last_indexed | 2024-12-13T04:48:36Z |
| publishDate | 2019-09-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj.art-de50d630a77649aab35abfdcf2bf902d2022-12-21T23:59:04ZengThe Royal SocietyOpen Biology2046-24412019-09-019910.1098/rsob.190156190156A consensus set of genetic vulnerabilities to ATR inhibitionNicole HustedtAlejandro Álvarez-QuilónAndrea McEwanJing Yi YuanTiffany ChoLisa KoobTraver HartDaniel DurocherThe response to DNA replication stress in eukaryotes is under the control of the ataxia–telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase ε accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity and the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic.https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.190156crispratrcancer therapydna replicationdna repair |
| spellingShingle | Nicole Hustedt Alejandro Álvarez-Quilón Andrea McEwan Jing Yi Yuan Tiffany Cho Lisa Koob Traver Hart Daniel Durocher A consensus set of genetic vulnerabilities to ATR inhibition Open Biology crispr atr cancer therapy dna replication dna repair |
| title | A consensus set of genetic vulnerabilities to ATR inhibition |
| title_full | A consensus set of genetic vulnerabilities to ATR inhibition |
| title_fullStr | A consensus set of genetic vulnerabilities to ATR inhibition |
| title_full_unstemmed | A consensus set of genetic vulnerabilities to ATR inhibition |
| title_short | A consensus set of genetic vulnerabilities to ATR inhibition |
| title_sort | consensus set of genetic vulnerabilities to atr inhibition |
| topic | crispr atr cancer therapy dna replication dna repair |
| url | https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.190156 |
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