KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency
Abstract ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but th...
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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/s41467-024-55637-5 |
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| author | Samah W. Awwad Colm Doyle Josie Coulthard Aldo S. Bader Nadia Gueorguieva Simon Lam Vipul Gupta Rimma Belotserkovskaya Tuan-Anh Tran Shankar Balasubramanian Stephen P. Jackson |
| author_facet | Samah W. Awwad Colm Doyle Josie Coulthard Aldo S. Bader Nadia Gueorguieva Simon Lam Vipul Gupta Rimma Belotserkovskaya Tuan-Anh Tran Shankar Balasubramanian Stephen P. Jackson |
| author_sort | Samah W. Awwad |
| collection | DOAJ |
| description | Abstract ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers. |
| format | Article |
| id | doaj-art-fddca3f8232148f2abac6cde0cefc503 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-fddca3f8232148f2abac6cde0cefc5032025-01-12T12:32:03ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-024-55637-5KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiencySamah W. Awwad0Colm Doyle1Josie Coulthard2Aldo S. Bader3Nadia Gueorguieva4Simon Lam5Vipul Gupta6Rimma Belotserkovskaya7Tuan-Anh Tran8Shankar Balasubramanian9Stephen P. Jackson10Cancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeThe Gurdon Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeCancer Research UK Cambridge Institute, University of CambridgeAbstract ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers.https://doi.org/10.1038/s41467-024-55637-5 |
| spellingShingle | Samah W. Awwad Colm Doyle Josie Coulthard Aldo S. Bader Nadia Gueorguieva Simon Lam Vipul Gupta Rimma Belotserkovskaya Tuan-Anh Tran Shankar Balasubramanian Stephen P. Jackson KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency Nature Communications |
| title | KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency |
| title_full | KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency |
| title_fullStr | KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency |
| title_full_unstemmed | KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency |
| title_short | KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency |
| title_sort | klf5 loss sensitizes cells to atr inhibition and is synthetic lethal with arid1a deficiency |
| url | https://doi.org/10.1038/s41467-024-55637-5 |
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