کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10157719 | 1666477 | 2018 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors
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کلمات کلیدی
5-FU5-FluouracilRPMI 1640Mitomycin CICLMSITBS-TMMCNTCFBSPBSDSBMicrosatellite instability - بی ثباتی ریزماهواره ایColorectal cancer - سرطان روده بزرگfetal bovine serum - سرم جنین گاوdouble-strand break - شکست دو ردیفPhosphate buffered saline - فسفات بافر شورRoswell Park Memorial Institute - مؤسسه یادبود پارک Roswellpol - پلPolymerase - پلیمرازCRC - کد افزونگی دورهای
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
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چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neoplasia - Volume 20, Issue 11, November 2018, Pages 1135-1143
Journal: Neoplasia - Volume 20, Issue 11, November 2018, Pages 1135-1143
نویسندگان
Albert Job, Lisa-Maria Schmitt, Lisa von Wenserski, Brigitte Lankat-Buttgereit, Thomas M. Gress, Malte Buchholz, Eike Gallmeier,