BRCA1 transports the DNA damage signal for CDDP-induced centrosome amplification through the centrosomal Aurora A,Cancer Science

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BRCA1 transports the DNA damage signal for CDDP-induced centrosome amplification through the centrosomal Aurora A
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-09 , DOI: 10.1111/cas.15573
Huicheng Qi _{1,

2} , Megumi Kikuchi _{1,

3} , Yuki Yoshino _{1,

2,

3} , Zhenzhou Fang _{1,

2} , Kazune Ohashi _{1,

3} , Takato Gotoh _{1,

3} , Ryo Ideta _{1,

4} , Ayako Ui ₅ , Shino Endo _{1,

2} , Kei Otsuka _{1,

3} , Norihisa Shindo ₆ , Kohsuke Gonda ₇ , Chikashi Ishioka ₈ , Yoshio Miki ₉ , Tokuro Iwabuchi ₁₀ , Natsuko Chiba _{1,

2,

3}

Affiliation

Department of Cancer Biology; Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Department of Cancer Biology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Laboratory of Cancer Biology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
Tohoku University School of Medicine, Sendai, Japan.
Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
Department of Medical Physics, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Faculty of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan.

Breast cancer gene 1 (BRCA1) plays roles in DNA repair and centrosome regulation and is involved in DNA damage-induced centrosome amplification (DDICA). Here, the centrosomal localization of BRCA1 and the kinases involved in centrosome duplication were analyzed in each cell cycle phase after treatment with DNA crosslinker cisplatin (CDDP). CDDP treatment increased the centrosomal localization of BRCA1 in early S–G2 phase. BRCA1 contributed to the increased centrosomal localization of Aurora A in S phase and that of phosphorylated Polo-like kinase 1 (PLK1) in late S phase after CDDP treatment, resulting in centriole disengagement and overduplication. The increased centrosomal localization of BRCA1 and Aurora A induced by CDDP treatment involved the nuclear export of BRCA1 and BRCA1 phosphorylation by ataxia telangiectasia mutated (ATM). Patient-derived variants and mutations at phosphorylated residues of BRCA1 suppressed the interaction between BRCA1 and Aurora A, as well as the CDDP-induced increase in the centrosomal localization of BRCA1 and Aurora A. These results suggest that CDDP induces the phosphorylation of BRCA1 by ATM in the nucleus and its transport to the cytoplasm, thereby promoting the centrosomal localization Aurora A, which phosphorylates PLK1. The function of BRCA1 in the translocation of the DNA damage signal from the nucleus to the centrosome to induce centrosome amplification after CDDP treatment might support its role as a tumor suppressor.

中文翻译：

BRCA1 通过中心体 Aurora A 传输 DNA 损伤信号，用于 CDDP 诱导的中心体扩增

乳腺癌基因 1 ( BRCA1 ) 在 DNA 修复和中心体调节中发挥作用，并参与 DNA 损伤诱导的中心体扩增 (DDICA)。在这里，在用 DNA 交联剂顺铂 (CDDP) 处理后的每个细胞周期阶段，分析了 BRCA1 的中心体定位和参与中心体复制的激酶。 CDDP 治疗增加了 BRCA1 在早期 S-G2 期的中心体定位。 CDDP 治疗后，BRCA1 导致 S 期 Aurora A 的中心体定位增加，以及 S 期晚期磷酸化 Polo 样激酶 1 (PLK1) 的中心体定位增加，导致中心粒脱离和过度复制。 CDDP 治疗诱导的 BRCA1 和 Aurora A 中心体定位增加涉及共济失调毛细血管扩张突变 (ATM) 导致的 BRCA1 和 BRCA1 磷酸化的核输出。患者衍生的 BRCA1 磷酸化残基变异和突变抑制了 BRCA1 和 Aurora A 之间的相互作用，以及 CDDP 诱导的 BRCA1 和 Aurora A 中心体定位的增加。这些结果表明 CDDP 通过 ATM 诱导 BRCA1 磷酸化在细胞核中转运至细胞质，从而促进 Aurora A 磷酸化 PLK1 的中心体定位。 BRCA1 在 CDDP 治疗后将 DNA 损伤信号从细胞核易位到中心体以诱导中心体扩增的功能可能支持其作为肿瘤抑制因子的作用。

更新日期：2022-09-09

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