BRCA1 degradation in response to mitochondrial damage in breast cancer cells
| Autor: | Keisuke Miyazawa, Hiroshi Handa, Edward Barroga, Koji Fujita, Hiromi Kazama, Kana Miyahara, Masahiko Kuroda, Yumiko Yamada, Hirotsugu Hino, Takashi Ishikawa, Mayumi Tokuhisa, Naoharu Takano, Masaki Hiramoto |
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| Rok vydání: | 2021 |
| Předmět: |
Cell biology
Carbonyl Cyanide m-Chlorophenyl Hydrazone endocrine system diseases DNA damage Ubiquitin-Protein Ligases Science Breast Neoplasms PINK1 Biochemistry Article Parkin Breast cancer Downregulation and upregulation Humans DNA Breaks Double-Stranded skin and connective tissue diseases Cancer Cell Nucleus Gene knockdown Multidisciplinary biology BRCA1 Protein Kinase Chemistry Ubiquitination Mitochondria Up-Regulation Ubiquitin ligase HEK293 Cells Proteolysis Cancer cell MCF-7 Cells biology.protein Cancer research Medicine Female Protein Kinases |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-021-87698-7 |
| Popis: | BRCA1 is a well-studied tumor suppressor involved in the homologous repair of DNA damage, whereas PINK1, a mitochondrial serine/threonine kinase, is known to be involved in mitochondrial quality control. Genetic mutations of PINK1 and Parkin cause autosomal recessive early-onset Parkinson’s disease. We found that in breast cancer cells, the mitochondrial targeting reagents, which all induce mitochondrial depolarization along with PINK1 upregulation, induced proteasomal BRCA1 degradation. This BRCA1 degradation was dependent on PINK1, and BRCA1 downregulation upon mitochondrial damage caused DNA double-strand breaks. BRCA1 degradation was mediated through the direct interaction with the E3 ligase Parkin. Strikingly, BRCA1 and PINK1/Parkin expression were inversely correlated in cancerous mammary glands from breast cancer patients. BRCA1 knockdown repressed cancer cell growth, and high BRCA1 expression predicted poor relapse-free survival in breast cancer patients. These observations indicate a novel mechanism by which mitochondrial damage is transmitted to the nucleus, leading to BRCA1 degradation. |
| Databáze: | OpenAIRE |
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