A feed-forward mechanism involving Drosophila fragile X mental retardation protein triggers a replication stress-induced DNA damage response
A feed-forward mechanism involving Drosophila fragile X mental retardation protein triggers a replication stress-induced DNA damage response
复制标题
涉及果蝇脆性 X 智力迟钝蛋白的前馈机制触发复制应激诱导的 DNA 损伤反应
DOI：
10.1093/hmg/ddu241
复制
发表时间：
2014-10-01
影响因子：
3.5
通讯作者：
Chen, Dahua
中科院分区：
文献类型：
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作者：
Zhang, Wenxin;Cheng, Ying;Chen, Dahua
脆性X综合征是一种常见的遗传性智力低下，由脆性X智力低下蛋白(FMRP)缺失引起。作为一种选择性的RNA结合蛋白，FMRP主要定位于细胞质中，在那里它调节翻译控制。然而，细胞核中存在一小部分FMRP，其功能一直难以捉摸。在这里，我们证明了果蝇细胞核中的dFMR1是复制应激诱导的DNA损伤反应(DDR)中的H2Av磷酸化所必需的。复制应激可诱导dFmr1的表达，促进dFMR1的核积聚。我们发现，在复制压力的刺激下，dFMR1以结构域特异性的方式与染色质结合，这是其诱导H_2Av磷酸化的关键。这些结果共同揭示了FMRP在DDR中意想不到的核心作用，并揭示了dFmr1与复制应激诱导的早期DDR相互调节，从而协同触发DDR信号级联反应的前馈机制。
Fragile X syndrome, a common form of inherited mental retardation, is caused by loss of the fragile X mental retardation protein (FMRP). As a selective RNA-binding protein, FMRP is localized predominately in cytoplasm, where it regulates translational control. However, there is a small portion of FMRP present in the nucleus, and its function there has been elusive. Here, we show that Drosophila dFMR1 in nucleus is required for replication stress-induced H2Av phosphorylation in the DNA damage response (DDR). Replication stress could induce the expression of dFmr1 and promote the nuclear accumulation of dFMR1. We show that, upon the stimulation of replication stress, dFMR1 is associated with chromatin in a domain-specific manner, which is essential for its ability to induce the phosphorylation of H2Av. These results together reveal an unexpected nuclear role of FMRP in DDR and uncover a feed-forward mechanism by which dFmr1 and early DDR induced by replication stress reciprocally regulate each other, thereby synergistically triggering activity of the DDR signaling cascade.