Molecular mechanisms of severe genomic instability induced by embedded ribonucleotides

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K12339
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63030:Chemical substance influence on environment-related
• Research Institution: Chiba University
• Principal Investigator: Sassa Akira 千葉大学, 大学院理学研究院, 准教授 (10738347)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: DNA損傷 / ゲノム不安定性 / DNA修復 / 突然変異

Outline of Final Research Achievements

Ribonucleoside triphosphate is essential as the substrate for energy production and RNA synthesis. However, it can also be incorporated into the genome during DNA replication. In this study, we focused on genomic instability induced by the accumulation of ribonucleotides and its underlying mechanisms. First, we newly identified that nucleotide excision repair has an activity to excise an oxidized ribonucleotide embedded into DNA, which suppresses ribonucleotide-induced mutagenesis in cells. Second, we revealed that Tyrosyl-DNA phosphodiesterases TDP1 and TDP2 are involved in the ribonucleotide-induced mutagenesis in cells.

Free Research Field

化学物質影響関連

Academic Significance and Societal Importance of the Research Achievements

DNA中に取り込まれたリボヌクレオチドはDNA複製の妨害や染色体異常を引き起こし、深刻な神経変性疾患の発症や細胞のがん化につながることが報告されている。本研究において示唆されたゲノム不安定化の抑制及び誘発のメカニズムは、疾患発症の仕組みを明らかにするための分子基盤になると共に、治療法の開発につながる重要な知見となり得る。