title: Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1.
abstract: 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). We identified 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.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Barclay
authors.forename: Takuya
authors.initials: T
authors.lastname: Tamura
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ito
authors.forename: Kyota
authors.initials: K
authors.lastname: Fujita
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.forename: Asuka
authors.initials: A
authors.lastname: Katsuta
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shiwaku
authors.forename: Masaki
authors.initials: M
authors.lastname: Sone
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067696:Ataxin-1; D000067528:Ataxins; D002453:Cell Cycle / Q000235:genetics; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008136:Longevity / Q000235:genetics; D008297:Male; D016254:Mutagenesis, Insertional; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D015398:Signal Transduction; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D049490:Systems Biology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse