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Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1

  • P3-313
  • 田村 拓也 / Takuya Tamura:1 Barclay Sam S / Sam S Barclay:2 伊藤 日加瑠 / Hikaru Ito:1 Fujita Kyota / Kyota Fujita:1 Tagawa Kazuhiko / Kazuhiko Tagawa:1 島村 徹平 / Teppei Shimamura:4 勝田 明寿香 / Asuka Katsuta:3 塩飽 裕紀 / Hiroki Shiwaku:1 曽根 雅紀 / Masaki Sone:3 井元 清哉 / Seiya Imoto:4 宮野 悟 / Satoru Miyano:4 岡澤 均 / Hitoshi Okazawa:1 
  • 1:東京医科歯科大学 / Tokyo Medical and Dental University 2:Imperial College School of Medicine, London, UK / Imperial College School of Medicine, London, UK 3:東邦大学理学部生物分子科学科 / Dept Biomolecular Science, Toho University, Funabashi, Japan 4:東京大医科研 / Inst Medical Science, Univ of Tokyo, Tokyo, Japan 

DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1).Weidentified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.

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