Formation and repair mechanisms of radiation-induced DNA-protein cross-links

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H03374
• 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: Hiroshima University
• Principal Investigator: IDE Hiroshi 広島大学, 統合生命科学研究科(理), 教授 (30223126)
• Co-Investigator(Kenkyū-buntansha): 平山 亮一 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 重粒子線治療研究部, 主任研究員(定常) (90435701)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 放射線 / DNA損傷 / 修復機構

Outline of Final Research Achievements

DNA molecules that carry the genetic information of the cell are constantly associated with various proteins. DNA-associated proteins are covalently trapped in DNA to form DNA-protein cross-links (DPCs) when cells are irradiated with ionizing radiation or treated with other DNA-damaging agents. However, little is known about the amount of DPC damage resulting from the exposure to ionizing radiation and other DNA-damaging agents. Furthermore, how DPC damage is repaired in cells remains largely elusive. In the present study, we irradiated cells with X-rays and analyzed the proteins involved in DPCs. The possible mechanisms of DPC formation are discussed. We also used cells that were deficient in tyrosyl-DNA phosphodiesterases (TDP) 1 and 2 together with other enzymes, and elucidated the roles of these enzymes in the repair of DPCs that contained the cleavage complex of topoisomerases 1 and 2 (TOP1cc and TOP2cc).

Free Research Field

放射線生物学

Academic Significance and Societal Importance of the Research Achievements

DNA-タンパク質架橋（DPC）は，放射線，紫外線，ホルムアルデヒドなどの変異原物質で誘発される主要なDNA損傷の一つである。本研究により，DPCの生成機構と修復機構の一端が明らかになった。DNA損傷は，発がんや老化の原因となることが知られていることから，DPC形成に起因する発がんおよび老化機構の解明につながると予想される。また，カンプトテシンやエトポシドなどの抗がん剤は，DPCを形成することによりがん細胞を死滅させる。DPC修復に関わる酵素を標的とした阻害剤を分子設計することにより，効果の高いがん治療が可能となるとなる。