Mutagenesis by translesion synthesis bypass endogenous DNA structures by DNA polymerase zeta

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K12181
• 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: Hiroshima University
• Principal Investigator: Suzuki Tetsuya 広島大学, 医系科学研究科(薬), 助教 (20573950)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: DNA損傷 / 非B型DNA / 変異 / 損傷乗り越えDNA合成 / DNAポリメラーゼ ζ

Outline of Final Research Achievements

Deficiency of DNA polymerase (Pol) ζ, which is one of translesion DNA polymerases, causes genomic instability. In this study, the roles of Polζin mutagenesis and genomic instability in replication across endogenous chemical and higher-order structures were analyzed. Polζcould not be significantly involved in the bypass of 8-oxo-7,8-dihydroguanine and abasic site, endogenous DNA damages that occurs frequently, and ribonucleotides that are incorporated into DNA during replication. On the other hand, the mutation frequencies of plasmid with non-B-form DNA, such as Z-form and triplex structures, were changed in Polζmutant cells (low-fidelity and weak-catalytic-activity mutants). This result suggests that Polζcan be involved in replication of Z-form and triplex structures.

Free Research Field

生物系薬学、分子生物学、DNA損傷学

Academic Significance and Societal Importance of the Research Achievements

Polζが内在的に多く生じるDNA損傷である8-oxo-7,8-dihydroguanine、脱塩基部位およびリボヌクレオチドの複製には関与しないことおよび非B型構造であるZ形構造や三重鎖構造の複製に関与する可能性を明らかにした。これらの研究成果は、内在的に生じるDNA損傷などよりも非B型DNA構造の方がPolζ欠損時のゲノム不安定性に関与している可能性を示唆しており、通常の複製条件下で起こるゲノム不安定性の要因を解明するうえで重要な結果であると考えられる。今後、さらに他のDNA構造とPolζとの関連を研究することによりゲノム不安定化機構の解明と発癌との関連を明らかにできることが期待される。