A Novel Role of Krüppel-like Factor 8 in DNA Repair in Breast Cancer Cells*
| Autor: | Chao Shen, Hui Xie, Melissa S. Wason, Liu Hu, Heng Lu, Lin Yu, Tianshu Li, Satadru K. Lahiri, Debarati Mukherjee, Jihe Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
DNA Repair
DNA damage DNA repair Poly ADP ribose polymerase Kruppel-Like Transcription Factors Poly (ADP-Ribose) Polymerase-1 Breast Neoplasms DNA-Activated Protein Kinase Biochemistry Mice Cell Line Tumor medicine Animals Humans Phosphorylation Molecular Biology DNA-PKcs Mice Knockout Antibiotics Antineoplastic biology Cancer Sumoylation Cell Biology DNA repair protein XRCC4 Fibroblasts medicine.disease Embryo Mammalian Proliferating cell nuclear antigen Neoplasm Proteins Repressor Proteins Doxorubicin Drug Resistance Neoplasm Cancer cell biology.protein Cancer research Poly(ADP-ribose) Polymerases Signal Transduction Transcription Factors |
| Popis: | Krüppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, the role of KLF8 in cancer remains largely unknown. Here, we report a surprisingly novel role for KLF8 in DNA repair in breast cancer cells. Comet, clonogenic, and WST-1 assays showed that KLF8 expression is required for protecting human breast cancer cells from doxorubicin-induced DNA damage and cell death. Western blotting indicated that overexpression of ectopic KLF8 attenuated the levels of the DNA damage marker γH2A.X in doxorubicin-treated PARP-1(+/+) but not PARP-1(-/-) mouse embryonic fibroblasts, whereas the PARP-1-binding-defective KLF8 mutant failed to do so. Interestingly, in response to the DNA damage, KLF8 was phosphorylated by the DNA-dependent protein kinase catalytic subunit and, subsequently, SUMOylated by SUMO E3 ligases protein inhibitors of activated STAT (PIASs), which depends upon the interaction of KLF8 with DNA-dependent protein kinase catalytic subunit, PIASs, and PARP-1 as well as their enzymatic activities. Lastly, we show evidence that KLF8 was recruited to the DNA damage site. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair and therapeutic resistance in breast cancer cells. |
| Databáze: | OpenAIRE |
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