BRCA1 degradation in response to mitochondrial damage in breast cancer cells

Abstract 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...

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Autores principales:	Kana Miyahara, Naoharu Takano, Yumiko Yamada, Hiromi Kazama, Mayumi Tokuhisa, Hirotsugu Hino, Koji Fujita, Edward Barroga, Masaki Hiramoto, Hiroshi Handa, Masahiko Kuroda, Takashi Ishikawa, Keisuke Miyazawa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b53b82c6ae5403ab382220048b0b353
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spelling	oai:doaj.org-article:2b53b82c6ae5403ab382220048b0b3532021-12-02T16:45:40ZBRCA1 degradation in response to mitochondrial damage in breast cancer cells10.1038/s41598-021-87698-72045-2322https://doaj.org/article/2b53b82c6ae5403ab382220048b0b3532021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87698-7https://doaj.org/toc/2045-2322Abstract 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.Kana MiyaharaNaoharu TakanoYumiko YamadaHiromi KazamaMayumi TokuhisaHirotsugu HinoKoji FujitaEdward BarrogaMasaki HiramotoHiroshi HandaMasahiko KurodaTakashi IshikawaKeisuke MiyazawaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kana Miyahara Naoharu Takano Yumiko Yamada Hiromi Kazama Mayumi Tokuhisa Hirotsugu Hino Koji Fujita Edward Barroga Masaki Hiramoto Hiroshi Handa Masahiko Kuroda Takashi Ishikawa Keisuke Miyazawa BRCA1 degradation in response to mitochondrial damage in breast cancer cells
description	Abstract 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.
format	article
author	Kana Miyahara Naoharu Takano Yumiko Yamada Hiromi Kazama Mayumi Tokuhisa Hirotsugu Hino Koji Fujita Edward Barroga Masaki Hiramoto Hiroshi Handa Masahiko Kuroda Takashi Ishikawa Keisuke Miyazawa
author_facet	Kana Miyahara Naoharu Takano Yumiko Yamada Hiromi Kazama Mayumi Tokuhisa Hirotsugu Hino Koji Fujita Edward Barroga Masaki Hiramoto Hiroshi Handa Masahiko Kuroda Takashi Ishikawa Keisuke Miyazawa
author_sort	Kana Miyahara
title	BRCA1 degradation in response to mitochondrial damage in breast cancer cells
title_short	BRCA1 degradation in response to mitochondrial damage in breast cancer cells
title_full	BRCA1 degradation in response to mitochondrial damage in breast cancer cells
title_fullStr	BRCA1 degradation in response to mitochondrial damage in breast cancer cells
title_full_unstemmed	BRCA1 degradation in response to mitochondrial damage in breast cancer cells
title_sort	brca1 degradation in response to mitochondrial damage in breast cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2b53b82c6ae5403ab382220048b0b353
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BRCA1 degradation in response to mitochondrial damage in breast cancer cells

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