DNA double strand break repair factors mutated in a new syndrome with microcephaly

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H01877
• 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: Nagoya University (2018-2019); Nagasaki University (2017)
• Principal Investigator: NAKAZAWA Yuka 名古屋大学, 環境医学研究所, 助教 (00533902)
• Co-Investigator(Kenkyū-buntansha): 岡 泰由 名古屋大学, 環境医学研究所, 講師 (60762383) ; 荻 朋男 名古屋大学, 環境医学研究所, 教授 (80508317)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: DNA修復 / 小頭症 / コケイン症候群 / RNAポリメラーゼ

Outline of Final Research Achievements

In this study, we have focused on microcephaly as a commonly observed clinical feature of DNA repair deficiency disorders. We have identified several new pathogenic variants in DNA repair genes from microcephaly cases and tried to elucidate their molecular pathogenesis. We have generated mice with mutations in those newly determined genes; however, we often experienced lack of expected phenotypes. This is partly due to greater tolerance to DNA damages in mice; we decided to cross the animals with other mice with deficiency in different DNA repair processes so that overload DNA damage to elicit a phenotype. From this approach, we found that microcephaly and some types of neurodegeneration diseases can be explained by prolonged arrest of RNA polymerases at DNA damage sites during transcription. DNA damage stalled RNA polymerases are ubiquitinated to facilitate DNA repair; when this process is compromised, various neurodegenerative phenotypes, as shown in Cockayne syndrome, come up.

Free Research Field

DNA修復、分子生物学、人類遺伝学

Academic Significance and Societal Importance of the Research Achievements

DNA 損傷応答・DNA 修復機構の先天的な異常により、ゲノムが不安定化することで発症する様々な遺伝性疾患が知られている。これらの疾患では小頭症を示す症例が多く、鑑別診断が重要である。今回、収集した症例のゲノム解析などから、いくつかのDNA修復機構に新規の疾患原因変異を同定した。モデルマウスの解析から、コケイン症候群などで観察される小頭症と神経変性を説明可能な転写と共役したDNA修復機構の分子メカニズムの詳細が明らかにされた。