Role of protein phosphorylating function of DNA-PK in DNA double-strand break repair

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H02817
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Matsumoto Yoshihisa 東京工業大学, 科学技術創成研究院, 准教授 (20302672)
• Research Collaborator: SHIMADA MIKIO ; SHARMA MUKESH KUMAR ; AMIRI MOGHAHANI ALI REZA ; ASA ANIE DAY DE CASTRO
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 放射線 / がん / DNA / DNA修復 / タンパク質リン酸化 / シグナル伝達

Outline of Final Research Achievements

This study aimed to clarify the substrate and role of protein phosphorylation by DNA-PK, which is considered the molecular sensor for DNA double-strand break (DSB). Regarding XRCC4, which is involved in the joining reaction of two DNA ends at the final step of DSB repair, we generated the phosphorylation-specific antibodies, corresponding to six phosphorylation sites identified by us and other groups. By using these antibodies, we clarified the response of phosphorylation to radiation. Through the generation and analyses of phosphorylation-disabled mutants, we also clarified the phosphorylation sites, which are essential for DSB repair. Additionally, through the generation and analyses of XRCC4 mutants, mimicking the mutations found in patients of microcephaly and growth defects, we clarified the impact of disease-associated mutations on the function of XRCC4 in DSB repair.

Free Research Field

分子放射線生物学

Academic Significance and Societal Importance of the Research Achievements

DNA二重鎖切断(DSB)は、放射線によって生じる種々のDNA損傷の中で最も重篤であり、がん放射線治療の成否の鍵を握ると考えられている。DNA-PKはDSBの「センサー」として注目されてきたが、DSB修復過程において、どのタンパク質を、何のためにリン酸化するかは20年以上未解明のままであった。本研究で、DSBの修復過程の最終段階でのDNA末端の結合に関わるXRCC4のリン酸化の放射線に対する応答、DSB修復における重要性が明らかになった。本研究の成果は、DSB修復過程の理解の深化とともに、がん放射線治療における放射線感受性の予測や増感剤開発などに示唆を与えるものである。