Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection
Summary: Cells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predi...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-02-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720300772 |
| _version_ | 1818189962133110784 |
|---|---|
| author | Mu-Yan Cai Connor E. Dunn Wenxu Chen Bose S. Kochupurakkal Huy Nguyen Lisa A. Moreau Geoffrey I. Shapiro Kalindi Parmar David Kozono Alan D. D’Andrea |
| author_facet | Mu-Yan Cai Connor E. Dunn Wenxu Chen Bose S. Kochupurakkal Huy Nguyen Lisa A. Moreau Geoffrey I. Shapiro Kalindi Parmar David Kozono Alan D. D’Andrea |
| author_sort | Mu-Yan Cai |
| collection | DOAJ |
| description | Summary: Cells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-wide CRISPR screen to identify genetic vulnerabilities that sensitize lung cancer cells to ATM inhibitors. Knockout of genes in the Fanconi anemia (FA)/BRCA pathway results in hypersensitivity to the ATM inhibitor M3541. Knockdown of either an FA gene or of ATM results in reduced double-strand break end resection, enhanced non-homologous end joining (NHEJ) repair, and decreased homologous recombination repair. Knockout of both the FA/BRCA pathway and ATM strongly inhibits end resection and generates toxic levels of NHEJ, thereby elucidating a mechanism of cellular death by synthetic lethality. ATM inhibitors may therefore be useful for the treatment of tumors with a defective FA/BRCA pathway. : ATM inhibitors are currently in clinical development as anti-cancer agents. Using a genome-wide CRISPR screen, Cai et al. demonstrate that cancer cells with Fanconi anemia (FA) pathway deficiency are sensitive to ATM inhibition. The authors also show that synthetic lethality between ATM and the FA pathway is due to reduced DNA resection and increased toxic NHEJ. Keywords: ATM inhibitor, CRISPR sgRNA screening, Fanconi anemia pathway, NHEJ, end resection |
| first_indexed | 2024-12-11T23:51:09Z |
| format | Article |
| id | doaj.art-6bb81879c78a40209c975837c5b87fc5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T23:51:09Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6bb81879c78a40209c975837c5b87fc52022-12-22T00:45:29ZengElsevierCell Reports2211-12472020-02-0130724022415.e5Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End ResectionMu-Yan Cai0Connor E. Dunn1Wenxu Chen2Bose S. Kochupurakkal3Huy Nguyen4Lisa A. Moreau5Geoffrey I. Shapiro6Kalindi Parmar7David Kozono8Alan D. D’Andrea9Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, ChinaDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USACenter for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Corresponding authorSummary: Cells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-wide CRISPR screen to identify genetic vulnerabilities that sensitize lung cancer cells to ATM inhibitors. Knockout of genes in the Fanconi anemia (FA)/BRCA pathway results in hypersensitivity to the ATM inhibitor M3541. Knockdown of either an FA gene or of ATM results in reduced double-strand break end resection, enhanced non-homologous end joining (NHEJ) repair, and decreased homologous recombination repair. Knockout of both the FA/BRCA pathway and ATM strongly inhibits end resection and generates toxic levels of NHEJ, thereby elucidating a mechanism of cellular death by synthetic lethality. ATM inhibitors may therefore be useful for the treatment of tumors with a defective FA/BRCA pathway. : ATM inhibitors are currently in clinical development as anti-cancer agents. Using a genome-wide CRISPR screen, Cai et al. demonstrate that cancer cells with Fanconi anemia (FA) pathway deficiency are sensitive to ATM inhibition. The authors also show that synthetic lethality between ATM and the FA pathway is due to reduced DNA resection and increased toxic NHEJ. Keywords: ATM inhibitor, CRISPR sgRNA screening, Fanconi anemia pathway, NHEJ, end resectionhttp://www.sciencedirect.com/science/article/pii/S2211124720300772 |
| spellingShingle | Mu-Yan Cai Connor E. Dunn Wenxu Chen Bose S. Kochupurakkal Huy Nguyen Lisa A. Moreau Geoffrey I. Shapiro Kalindi Parmar David Kozono Alan D. D’Andrea Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection Cell Reports |
| title | Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection |
| title_full | Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection |
| title_fullStr | Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection |
| title_full_unstemmed | Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection |
| title_short | Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection |
| title_sort | cooperation of the atm and fanconi anemia brca pathways in double strand break end resection |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720300772 |
| work_keys_str_mv | AT muyancai cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT connoredunn cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT wenxuchen cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT boseskochupurakkal cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT huynguyen cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT lisaamoreau cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT geoffreyishapiro cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT kalindiparmar cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT davidkozono cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection AT alanddandrea cooperationoftheatmandfanconianemiabrcapathwaysindoublestrandbreakendresection |