Regulation of 53BP1 repositioning and foci formation during homologous recombination

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K12821
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Nagoya University (2019); Nagasaki University (2018); Sasaki Foundation (2017)
• Principal Investigator: ISONO Mayu 名古屋大学, 環境医学研究所, 特任助教 (90713511)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: DNA二本鎖切断 / DSB修復 / 53BP1 / ATR活性

Outline of Final Research Achievements

DNA double-strand break (DSB) caused by ionizing radiation or anti-cancer drugs is a deleterious damage, which can lead to chromosomal instability. Cells have the two main repair pathways for DSB, non-homologous end-joining (NHEJ) and homologous recombination (HR). While NHEJ functions through cell cycle, HR ensues if NHEJ fails to repair DSB in S/G2 phase. 53BP1 is known as a factor promoting NHEJ via inhibiting HR. We show the activation of ATM and ATR is dispensable for the maintenance of 53BP1 foci at sites of DSBs generated by ionizing radiation at early time points (0.5 h). Interestingly, inhibition of ATR (but not ATM) disturbs the maintenance of 53BP1 foci at later time points (4 h), which is fully recovered when the inhibitor is omitted. Collectively, the results in this study suggest that localization of 53BP1 foci at DSB sites during HR is dependent on ATR activation.

Free Research Field

放射線照射によって誘発される細胞傷害、特に近年はDNA二本鎖切断修復機構に着目し研究を行っている。

Academic Significance and Societal Importance of the Research Achievements

今回の研究結果から、HR進行中のDSB部位における53BP1の集積の維持には、DSB誘発早期に活性化するATMではなくresectionの開始に伴い活性化するATRに依存することが示唆された。HR修復における53BP1の役割に関して、今後より詳細な解析を進めることができれば、発がん等の疾病発症のメカニズム解明の一助になると考えている。