Elucidation of the ubiquitin pathway that removes adducts attached to DNA double-strand breaks

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H04267
• 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: Tokyo Metropolitan Institute of Medical Science (2021); Kyoto University (2019-2020)
• Principal Investigator: SASANUMA Hiroyuki 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 副参事研究員 (00531691)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: がん / DNA修復 / 相同組換え

Outline of Final Research Achievements

DNA double strand breaks (DSBs) are mainly repaired by Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). While the ends of DSBs induced by restriction enzyme harbor 5’-phosphate and 3’-hydroxy group, those induced by ionizing radiation (IR) do not. IR induces DSBs with a variety of chemical modifications at DSB end-proximal regions. Such DSBs with chemical/protein adducts interfere DSB repair process. The molecular mechanism by which the adducts at DSB sites are processed remains elusive. The aim of this research project is to clarify its molecular mechanism of adduct removal from DSB-ends. We identified the molecules involved in adduct removal. Ubiquitin E2 ligase UBC13-dependent ubiquitination at the DSB end-proximal region promotes the removal of adducts and its repair by NHEJ. We proposed a model that the ubiquitinated proteins are recognized by RAP80-BRCA1, which transfers its DNA damaging signal to MRE11 nuclease to adduct removal.

Free Research Field

放射線生物学

Academic Significance and Societal Importance of the Research Achievements

抗がん治療では、放射線照射によりDNA損傷を与え腫瘍細胞を殺傷する。放射線感受性を高める増感剤は、治療効果を高めるのみならず照射線量を減らすことにつながる。本研究では、放射線によって切断端に発生する塩基損傷や蛋白質付加体の除去機構を明らかにした。本研究で同定したUBC13ユビキチン化酵素依存的な付加体除去の分子機構をもとに、放射線増感剤開発が可能となる。放射線生物学において、「切断端に発生する塩基損傷や蛋白質付加体の除去」の分子機構は長らく不明であったが、本研究によってその分子メカニズムの一端が明らかとなった。