Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors
The phosphoinositide 3-kinase–related kinase ATR is a central regulator of the DNA damage response. Its chemical inhibition eliminates subsets of cancer cells in various tumor types. This effect is caused at least partly by the synthetically lethal relationship between ATR and certain DNA repair gen...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-11-01
|
| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558618303853 |
| _version_ | 1818694175763202048 |
|---|---|
| author | Albert Job Lisa-Maria Schmitt Lisa von Wenserski Brigitte Lankat-Buttgereit Thomas M. Gress Malte Buchholz Eike Gallmeier |
| author_facet | Albert Job Lisa-Maria Schmitt Lisa von Wenserski Brigitte Lankat-Buttgereit Thomas M. Gress Malte Buchholz Eike Gallmeier |
| author_sort | Albert Job |
| collection | DOAJ |
| description | The phosphoinositide 3-kinase–related kinase ATR is a central regulator of the DNA damage response. Its chemical inhibition eliminates subsets of cancer cells in various tumor types. This effect is caused at least partly by the synthetically lethal relationship between ATR and certain DNA repair genes. In a previous screen using an siRNA library against DNA repair genes, we identified PRIM1, a part of the polymerase α-primase complex, as acting synthetically lethal with ATR. Applying a genetic ATR knock-in model of colorectal cancer cells, we confirmed that PRIM1 depletion inhibited proliferation of ATR-deficient cells and excluded artifacts due to clonal variation using an ATR reexpressing cell clone. We expanded these data by demonstrating in different cell lines that also chemical inhibition of ATR or its main effector kinase CHK1 reduces proliferation upon depletion of PRIM1. Mechanistically, PRIM1 depletion in ATR-deficient cells caused S-phase stasis in the absence of increased DNA damage followed by Wee1-mediated activation of caspase 8 and apoptosis. As PRIM1 inactivation sensitizes cancer cells to ATR and CHK1 inhibitors, mutations in PRIM1 or other components of the polymerase α-primase complex could represent novel targets for individualized tumor therapeutic approaches using ATR/CHK1 inhibitors, as has been previously demonstrated for POLD1, the catalytic subunit of polymerase δ. |
| first_indexed | 2024-12-17T13:25:24Z |
| format | Article |
| id | doaj.art-2b6c7f300e104b399bc8c52c314357dd |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-17T13:25:24Z |
| publishDate | 2018-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-2b6c7f300e104b399bc8c52c314357dd2022-12-21T21:46:45ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862018-11-01201111351143Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 InhibitorsAlbert Job0Lisa-Maria Schmitt1Lisa von Wenserski2Brigitte Lankat-Buttgereit3Thomas M. Gress4Malte Buchholz5Eike Gallmeier6Center for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyCenter for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyCenter for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyCenter for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyCenter for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyCenter for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyAddress all correspondence to: Prof. Dr. med. Eike Gallmeier, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Baldingerstraße, 35043, Marburg, Germany.; Center for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, GermanyThe phosphoinositide 3-kinase–related kinase ATR is a central regulator of the DNA damage response. Its chemical inhibition eliminates subsets of cancer cells in various tumor types. This effect is caused at least partly by the synthetically lethal relationship between ATR and certain DNA repair genes. In a previous screen using an siRNA library against DNA repair genes, we identified PRIM1, a part of the polymerase α-primase complex, as acting synthetically lethal with ATR. Applying a genetic ATR knock-in model of colorectal cancer cells, we confirmed that PRIM1 depletion inhibited proliferation of ATR-deficient cells and excluded artifacts due to clonal variation using an ATR reexpressing cell clone. We expanded these data by demonstrating in different cell lines that also chemical inhibition of ATR or its main effector kinase CHK1 reduces proliferation upon depletion of PRIM1. Mechanistically, PRIM1 depletion in ATR-deficient cells caused S-phase stasis in the absence of increased DNA damage followed by Wee1-mediated activation of caspase 8 and apoptosis. As PRIM1 inactivation sensitizes cancer cells to ATR and CHK1 inhibitors, mutations in PRIM1 or other components of the polymerase α-primase complex could represent novel targets for individualized tumor therapeutic approaches using ATR/CHK1 inhibitors, as has been previously demonstrated for POLD1, the catalytic subunit of polymerase δ.http://www.sciencedirect.com/science/article/pii/S1476558618303853 |
| spellingShingle | Albert Job Lisa-Maria Schmitt Lisa von Wenserski Brigitte Lankat-Buttgereit Thomas M. Gress Malte Buchholz Eike Gallmeier Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors Neoplasia: An International Journal for Oncology Research |
| title | Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors |
| title_full | Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors |
| title_fullStr | Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors |
| title_full_unstemmed | Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors |
| title_short | Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors |
| title_sort | inactivation of prim1 function sensitizes cancer cells to atr and chk1 inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S1476558618303853 |
| work_keys_str_mv | AT albertjob inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors AT lisamariaschmitt inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors AT lisavonwenserski inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors AT brigittelankatbuttgereit inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors AT thomasmgress inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors AT maltebuchholz inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors AT eikegallmeier inactivationofprim1functionsensitizescancercellstoatrandchk1inhibitors |