ROLE OF BRCA1 IN RADIATION-INDUCED CENTROSOMAL CHECKPOINT

BRCA1 在辐射诱导的中心体检查点中的作用

• 批准号: 14580569
• 负责人: SUZUKI Kenji
• 金额: $ 2.3万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580569/
• 关键词: RADIATION; BRCA1; CENTEROSOME; PHOSPHORYLATION

IONIZING RADIATION 'HAS BEEN KNOWN TO INDUCED DNA DOUBLE STRAND BREAKS, WHICH RESULT IN ACTIVATION OF ATM. ACTIVATED ATM PHOSPHORYLATES VARIOUS PROTEINS INCLUDING BRCA1. BRCA1 HAS BEEN FOUND TO BE INVOLVED IN INHERITED MAMMARY CARCINOMA, AND IT IS THOUGHT TO HAVE A FUNCTION IN REPAIR OF DNA DOUBLE STRAND BREAKS. HERE, WE SHOW THAT BRCA1 COLOCALIZE WITH CENTROSOMAS. WITHOUT BRCA1 CENTROSOMES TEND TO OVERAMPLIFY, WHICH LEAD TO MULTIPOLAR DIVISION. FURTHERMORE, WE FOUND THAT ACTIVATED FORMS OF ATM, PHOSPHORYLATED ATM AT SERINE1981, ALSO COLOCALIZED WITH CENTROSOMES, WHICH INDICATE THAT ACTIVATED ATM CONSTITUTIVELY PHOSPHORYLATE BRCA1. THESE RESULTS INDICATE THAT ATM-MEDIATED PHOSPHORYLATION OF BRCA1 MAY REGULATE CENTROSOMAL DUPLICATION NOT ONLY IN _UNIRRADIATED CELLS BUT ALSO AFTER IRRADIATION.

众所周知，电离辐射会引起 DNA 双链断裂，从而导致 ATM 激活。活化的 ATM 可使包括 BRCA1 在内的多种蛋白质磷酸化。 BRCA1 被发现与遗传性乳腺癌有关，并且被认为具有修复 DNA 双链断裂的功能。在这里，我们展示了 BRCA1 与中心体共定位。如果没有 BRCA1，中心体往往会过度扩增，从而导致多极分裂。此外，我们发现 ATM 的激活形式（位于 Serine1981 处的磷酸化 ATM）也与中心体共定位，这表明激活的 ATM 组成型磷酸化 BRCA1。这些结果表明，ATM 介导的 BRCA1 磷酸化不仅可以调节未照射细胞中的中心体复制，而且还可以调节照射后的中心体复制。

项目成果

Keiji Suzuki: "Delayed reactivation of p53 in the progeny of cells surviving ionizing radiation"Cancer Research. 63. 936-941 (2003)

Keiji Suzuki：“在电离辐射中幸存的细胞后代中 p53 的延迟重新激活”癌症研究。

Keiji Suzuki: "Radiation-induced DNA damage and delayed induced genomic instability"Oncogene. 22. 6988-6993 (2003)

Keiji Suzuki：“辐射诱导的 DNA 损伤和延迟诱导的基因组不稳定”癌基因。

Keiji Nakahata: "Heat shock induces centrosomal dysfunction, and causes non-apoptotic mitotic catastrophe in human tumor cells"International Journal of Hyperthermia. 18. 332-343 (2002)

Keiji Nakahata：“热休克导致中心体功能障碍，并导致人类肿瘤细胞发生非凋亡性有丝分裂灾难”《国际热疗杂志》。

K.Suzuki, M.Ojima, S.Kodama, M.Watanabe.: "Radiation-induced DNA damage and delayed induced genomic instability"Oncogene. 22. 6988-6993 (2003)

K.Suzuki、M.Ojima、S.Kodama、M.Watanabe.：“辐射诱导的 DNA 损伤和延迟诱导的基因组不稳定”癌基因。

Genro Kashino: "Relief of oxidative stress by ascorbic acid delayes cellular senescence of normal human and Werner syndrome fibroblast cells"Free Radical and Biological Medicine. 35. 438-443 (2003)

Genro Kashino：“抗坏血酸缓解氧化应激可延缓正常人类和沃纳综合征成纤维细胞的细胞衰老”自由基和生物医学。