Elucidation of Ubiquitin-Dependent DNA Damage Response as the Core Mechanism for Double-Strand Break Repair

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H04269
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: Osaka University
• Principal Investigator: Shinichiro Nakada 大阪大学, 高等共創研究院, 教授 (70548528)
• Co-Investigator(Kenkyū-buntansha): 宇井 彩子 東北大学, 加齢医学研究所, 准教授 (00469967)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: DNA2本鎖切断 / 相同組換 / DNA損傷 / PARP阻害剤 / DNA修復選択

Outline of Final Research Achievements

DNA double-strand breaks (DSBs) are DNA damages caused by events such as exposure to radiation. Failure to properly repair DNA can result in lethal damage. The ubiquitin-dependent pathway is an important signaling pathway that connects DSB detection and repair. In this study, we discovered a novel gene X that functions in this pathway. When the expression of gene X is suppressed, 53BP1 (non-homologous end joining inducer), which is involved in DSB repair pathway choice downstream of the ubiquitin-dependent pathway, excessively accumulates at the DSB site, while the accumulation of BRCA1 (homologous recombination inducer) decreases. Furthermore, the signaling of the homologous recombination process weakens, and the efficiency of homologous recombination also decreases, as demonstrated by these results.

Free Research Field

DNA修復

Academic Significance and Societal Importance of the Research Achievements

DSBは通常の細胞代謝では起こりにくいものの、わずかな残存が致死的となることや、遺伝子変異やゲノム構造異常を誘導する、非常に危険なDNA損傷である。細胞内ではDNA一本鎖切断が多発し、これが複製を経てDSBに変換され、相同組換えにより修復される。相同組換えに関わる遺伝子はゲノムの恒常性維持に必須であり、新規遺伝子の発見の意義は高い。また、遺伝子Xの発現抑制は、抗腫瘍薬として利用されているPARP1阻害剤への感受性を増強するというデータも得られている。本研究の発見は、DNA損傷を利用した抗がん戦略としての発展的な利用が期待できる。