Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7
The F‐box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate‐recognition subunit of Skp, cullin, F‐box (SCF)‐containing complexes. The tumour‐suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this m...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13537 |
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| author | Joseph S. Baxter Rachel Brough Dragomir B. Krastev Feifei Song Sandhya Sridhar Aditi Gulati John Alexander Theodoros I. Roumeliotis Zuza Kozik Jyoti S. Choudhary Syed Haider Stephen J. Pettitt Andrew N. J. Tutt Christopher J. Lord |
| author_facet | Joseph S. Baxter Rachel Brough Dragomir B. Krastev Feifei Song Sandhya Sridhar Aditi Gulati John Alexander Theodoros I. Roumeliotis Zuza Kozik Jyoti S. Choudhary Syed Haider Stephen J. Pettitt Andrew N. J. Tutt Christopher J. Lord |
| author_sort | Joseph S. Baxter |
| collection | DOAJ |
| description | The F‐box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate‐recognition subunit of Skp, cullin, F‐box (SCF)‐containing complexes. The tumour‐suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 screens, focussed RNA‐interference screens and whole and phospho‐proteome mass spectrometry profiling in multiple FBXW7 wild‐type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7‐related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small‐molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere‐associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7‐selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area. |
| first_indexed | 2024-03-08T04:49:30Z |
| format | Article |
| id | doaj.art-394126b61bef4541813ab49cbc06b55c |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-08T04:49:30Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-394126b61bef4541813ab49cbc06b55c2024-02-08T06:47:52ZengWileyMolecular Oncology1574-78911878-02612024-02-0118236938510.1002/1878-0261.13537Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7Joseph S. Baxter0Rachel Brough1Dragomir B. Krastev2Feifei Song3Sandhya Sridhar4Aditi Gulati5John Alexander6Theodoros I. Roumeliotis7Zuza Kozik8Jyoti S. Choudhary9Syed Haider10Stephen J. Pettitt11Andrew N. J. Tutt12Christopher J. Lord13The CRUK Gene Function Laboratory The Institute of Cancer Research London UKThe CRUK Gene Function Laboratory The Institute of Cancer Research London UKThe CRUK Gene Function Laboratory The Institute of Cancer Research London UKThe CRUK Gene Function Laboratory The Institute of Cancer Research London UKThe CRUK Gene Function Laboratory The Institute of Cancer Research London UKBreast Cancer Now Toby Robins Breast Cancer Research Centre The Institute of Cancer Research London UKBreast Cancer Now Toby Robins Breast Cancer Research Centre The Institute of Cancer Research London UKFunctional Proteomics Laboratory The Institute of Cancer Research London UKFunctional Proteomics Laboratory The Institute of Cancer Research London UKFunctional Proteomics Laboratory The Institute of Cancer Research London UKBreast Cancer Now Toby Robins Breast Cancer Research Centre The Institute of Cancer Research London UKThe CRUK Gene Function Laboratory The Institute of Cancer Research London UKBreast Cancer Now Toby Robins Breast Cancer Research Centre The Institute of Cancer Research London UKThe CRUK Gene Function Laboratory The Institute of Cancer Research London UKThe F‐box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate‐recognition subunit of Skp, cullin, F‐box (SCF)‐containing complexes. The tumour‐suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 screens, focussed RNA‐interference screens and whole and phospho‐proteome mass spectrometry profiling in multiple FBXW7 wild‐type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7‐related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small‐molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere‐associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7‐selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.https://doi.org/10.1002/1878-0261.13537cancerCDC7CRISPR screenFBXW7synthetic lethality |
| spellingShingle | Joseph S. Baxter Rachel Brough Dragomir B. Krastev Feifei Song Sandhya Sridhar Aditi Gulati John Alexander Theodoros I. Roumeliotis Zuza Kozik Jyoti S. Choudhary Syed Haider Stephen J. Pettitt Andrew N. J. Tutt Christopher J. Lord Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 Molecular Oncology cancer CDC7 CRISPR screen FBXW7 synthetic lethality |
| title | Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 |
| title_full | Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 |
| title_fullStr | Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 |
| title_full_unstemmed | Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 |
| title_short | Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7 |
| title_sort | cancer associated fbxw7 loss is synthetic lethal with pharmacological targeting of cdc7 |
| topic | cancer CDC7 CRISPR screen FBXW7 synthetic lethality |
| url | https://doi.org/10.1002/1878-0261.13537 |
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