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Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents
| Content Provider | Scilit |
|---|---|
| Author | Cui, Yuxia Palii, Stela S. Innes, Cynthia L. Paules, Richard S. |
| Copyright Year | 2014 |
| Description | DNA damage response (DDR) to double strand breaks is coordinated by 3 phosphatidylinositol 3-kinase-related kinase (PIKK) family members: the ataxia-telangiectasia mutated kinase (ATM), the ATM and Rad3-related (ATR) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). ATM and ATR are central players in activating cell cycle checkpoints and function as an active barrier against genome instability and tumorigenesis in replicating cells. Loss of ATM function is frequently reported in various types of tumors, thus placing more reliance on ATR for checkpoint arrest and cell survival following DNA damage. To investigate the role of ATR in the G2/M checkpoint regulation in response to ionizing radiation (IR), particularly when ATM is deficient, cell lines deficient of ATM, ATR, or both were generated using a doxycycline-inducible lentiviral system. Our data suggests that while depletion of ATR or ATM alone in wild-type human mammary epithelial cell cultures (HME-CCs) has little effect on radiosensitivity or IR-induced G2/M checkpoint arrest, depletion of ATR in ATM-deficient cells causes synthetic lethality following IR, which correlates with severe G2/M checkpoint attenuation. ATR depletion also inhibits IR-induced autophagy, regardless of the ATM status, and enhances IR-induced apoptosis particularly when ATM is deficient. Collectively, our results clearly demonstrate that ATR function is required for the IR-induced G2/M checkpoint activation and subsequent survival of cells with ATM deficiency. The synthetic lethal interaction between ATM and ATR in response to IR supports ATR as a therapeutic target for improved anti-cancer regimens, especially in tumors with a dysfunctional ATM pathway. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.4161/15384101.2014.960729?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615027/pdf |
| Ending Page | 3550 |
| Page Count | 10 |
| Starting Page | 3541 |
| ISSN | 15384101 |
| e-ISSN | 15514005 |
| DOI | 10.4161/15384101.2014.960729 |
| Journal | Cell Cycle |
| Issue Number | 22 |
| Volume Number | 13 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2014-10-29 |
| Access Restriction | Open |
| Subject Keyword | Journal: Cell Cycle Biochemistry and Molecular Biology Research and Experimental Medicine Atm and Rad3-related (atr) Atm, the Ataxia-telangiectasia Mutated Kinase Atp, Adenosine Triphosphate Atr, the Atm and Rad3-related Chk1, the Checkpoint Kinase 1 Chk2, the Checkpoint Kinase 2 Dapi, 4′,6-diamidino-2-phenylindole Ddr, Dna Damage Response Dna Damage Response Dna-pkcs, the Catalytic Subunit of the Dna-dependent Protein Kinase Dsbs, Double Strand Breaks G2/m Checkpoint Hme-ccs, Human Mammary Epithelial Cell Cultures Ir, Ionizing Radiation Rmi, Relative Mitotic Index Ssbs, Single Strand Breaks Wt, Wild-type Ionizing Radiation Synthetic Lethality |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Developmental Biology Medicine Molecular Biology |
