The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesion.

The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesion.
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DOI:
10.1093/nar/gkq738
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发表时间:
2011-01
影响因子:
14.9
通讯作者:
Pittman DL
Pittman DL
中科院分区:
生物学2区
文献类型:
--
作者:
Rajesh C;Baker DK;Pierce AJ;Pittman DL

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DNA 双链断裂 (DSB) 是最严重的 DNA 损伤形式之一,导致染色体易位,从而可能导致基因融合。 RAD51 家族通过 DSB 同源定向修复在保持基因组稳定性方面发挥着不可或缺的作用。通过蛋白质组学筛选,我们最近确定 SFPQ/PSF 是 RAD51 旁系同源物 RAD51D、RAD51C 和 XRCC2 的相互作用伙伴。 SFPQ 最初被发现是一种潜在的 RNA 剪接因子,后来被证明具有同源重组和非同源末端连接相关活性,并且还可以结合和调节 RAD51 的功能。在这里,我们证明 SFPQ 与 RAD51D 直接相互作用,并且两种蛋白质的缺陷都会导致细胞活力严重丧失,表明存在合成致死关系。令人惊讶的是,单独的 SFPQ 缺陷也会导致姐妹染色单体凝聚力缺陷和染色体不稳定。此外,SFPQ 被证明可以介导由 DNA 交联剂、烷化剂和喜树碱引起的同源定向 DNA 修复和 DNA 损伤反应。总而言之,这些数据表明 SFPQ 与 RAD51 蛋白复合物的关联对于 DNA 损伤的同源重组修复和维持基因组完整性至关重要。
DNA double-stranded breaks (DSBs) are among the most severe forms of DNA damage and responsible for chromosomal translocations that may lead to gene fusions. The RAD51 family plays an integral role in preserving genome stability by homology directed repair of DSBs. From a proteomics screen, we recently identified SFPQ/PSF as an interacting partner with the RAD51 paralogs, RAD51D, RAD51C and XRCC2. Initially discovered as a potential RNA splicing factor, SFPQ was later shown to have homologous recombination and non-homologous end joining related activities and also to bind and modulate the function of RAD51. Here, we demonstrate that SFPQ interacts directly with RAD51D and that deficiency of both proteins confers a severe loss of cell viability, indicating a synthetic lethal relationship. Surprisingly, deficiency of SFPQ alone also leads to sister chromatid cohesion defects and chromosome instability. In addition, SFPQ was demonstrated to mediate homology directed DNA repair and DNA damage response resulting from DNA crosslinking agents, alkylating agents and camptothecin. Taken together, these data indicate that SFPQ association with the RAD51 protein complex is essential for homologous recombination repair of DNA damage and maintaining genome integrity.
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