Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1
Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1
复制标题
DOI：
10.1093/hmg/ddt524
复制
发表时间：
2014-03-01
影响因子：
3.5
通讯作者：
Okazawa, Hitoshi
中科院分区：
文献类型：
--
作者：
Barclay, Sam S.;Tamura, Takuya;Okazawa, Hitoshi
DNA损伤修复与神经退行性疾病有关;然而，各种DNA修复系统对这些疾病的病理学的相对贡献尚未系统地研究。在这项研究中，我们进行了系统的所有可用的果蝇同源DNA修复基因的体内筛选，我们测试了它们的过度表达对脊髓小脑共济失调1型（SCA 1）表达人类突变型共济失调蛋白-1（Atxn 1）的果蝇模型的寿命和发育能力的影响。我们鉴定了以前未知的参与CAG-/polyQ相关发病机制的基因，这些基因在多种DNA损伤修复系统中发挥作用。除了每个修复系统的重要性之外，系统生物学分析揭示了基因筛选中连接阳性基因的核心网络，这些基因可能有助于SCA 1病理学。特别是，在SCA 1果蝇模型中对寿命影响最大的RpA 1位于与这种核心修复系统（包括同源重组（HR））相关的枢纽位置。我们发现Atxn 1实际上与RpA 1及其重要伙伴BRCA 1/2相互作用。此外，突变体，而不是正常Atxn 1受损的动态RpA 1在DNA损伤后的核。摄取BrdU浦肯野细胞中观察到的突变Atxn 1敲入小鼠，这表明他们异常进入S期。此外，Chk 1的化学和遗传抑制延长了寿命并恢复了眼睛退化。总的来说，我们阐明了SCA 1中DNA损伤修复的核心网络，其中可能包括HR的异常使用。
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.