DNA double strand break repair factors mutated in a new syndrome with microcephaly
Project/Area Number |
17H01877
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Risk sciences of radiation and chemicals
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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)
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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)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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Keywords | DNA修復 / 小頭症 / コケイン症候群 / RNAポリメラーゼ / 修復 |
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.
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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。
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair2020
Author(s)
Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
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Journal Title
Cell
Volume: 19
Issue: 6
Pages: 1228-1244
DOI
NAID
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.2020
Author(s)
Kato K, Okuno Y, Vasilev FF, Otomo T, Oishi H, Muramatsu H, Kawano Y, Oka Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
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Journal Title
Journal of Medical genetics
Volume: 57
Issue: 4
Pages: 245-253
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome.2018
Author(s)
Calmels N, Botta E, Jia N, Fawcett H, Nardo T, Nakazawa Y, Lanzafame M, Moriwaki S, Sugita K, Kubota M, Obringer C, Spitz MA, Stefanini M, Laugel V, Orioli D, Ogi T, Lehmann A.
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Journal Title
Journal of Medical Genetics
Volume: 55
Issue: 5
Pages: 329-343
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair.2017
Author(s)
Tsuda M, Cho K, Ooka M, Shimizu N, Watanabe R, Yasui A, Nakazawa Y, Ogi T, Harada H, Agama K, Nakamura J, Asada R, Fujiike H, Sakuma T, Yamamoto T, Murai J, Hiraoka M, Koike K, Pommier Y, Takeda S, Hirota K.
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Journal Title
PLos One
Volume: 12
Issue: 11
Pages: e0188320-e0188320
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells2017
Author(s)
Doi Ryoichiro, Tsuchiya Tomoshi, Mitsutake Norisato, Nishimura Satoshi, Matsuu-Matsuyama Mutsumi, Nakazawa Yuka, Ogi Tomoo, Akita Sadanori, Yukawa Hiroshi, Baba Yoshinobu, Yamasaki Naoya, Matsumoto Keitaro, Miyazaki Takuro, Kamohara Ryotaro, Hatachi Go, Sengyoku Hideyori et al.
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Journal Title
Scientific Reports
Volume: 7
Issue: 1
Pages: 1-15
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] 転写共役ヌクレオチド除去修復機構に重要なRNAポリメラーゼユビキチン化部位の同定.2019
Author(s)
中沢由華, 原雄一郎, 岡泰由, 小峯起, Diana van den Heuvel, 郭朝万, 大学保一, 磯野真由, 何予希, 嶋田繭子, 加藤香奈, 賈楠, 橋下悟, 小谷祐子, 三好由夏, 田中都, 祖父江顕, 光武範吏, 菅波孝祥, 増田章男, 大野欽司, 中田慎一郎, 真下知士, 山中宏二, Martijn S. Luijsterburg, 荻朋男.
Organizer
第42回日本分子生物学会年会
Related Report
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[Presentation] ChIP-seqを利用したDNA損傷およびヌクレオチド除去修復のモニタリング.2019
Author(s)
原雄一郎, 中沢由華, 岡泰由, 小峯起, Diana van den Heuvel, 郭朝万, 大学保一, 磯野真由, 何予希, 嶋田繭子, 加藤香奈, 賈楠, 橋下悟, 小谷祐子, 三好由夏, 田中都, 祖父江顕, 光武範吏, 菅波孝祥, 増田章男, 大野欽司, 中田慎一郎, 真下知士, 山中宏二, Martijn S. Luijsterburg, 荻朋男.
Organizer
第42回日本分子生物学会年会
Related Report
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[Presentation] VPS35Lの両アレルにおける機能喪失型バリアントは 3C/Ritscher-Schinzel 症候群に類似の先天異常症候群の原因となる.2019
Author(s)
加藤耕治, 岡泰由, 村松秀城, Vasilev F, 大友孝信, 大石久史, 河野好彦, 中沢由華, 荻朋男, 高橋義行, 齋藤伸治.
Organizer
日本人類遺伝学会第64回大会
Related Report
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[Presentation] Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.2019
Author(s)
Kato K, Oka Y, Muramatsu H, Vasilev F, Otomo T, Oishi H, Kawano Y, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S.
Organizer
ASHG 2019 Annual Meeting
Related Report
Int'l Joint Research
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