Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity.
Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity.
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DOI：
10.1093/nar/gky569
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发表时间：
2018-09-06
影响因子：
14.9
通讯作者：
Higgins GS
中科院分区：
文献类型：
--
作者：
Rodriguez-Berriguete G;Granata G;Puliyadi R;Tiwana G;Prevo R;Wilson RS;Yu S;Buffa F;Humphrey TC;McKenna WG;Higgins GS
核孔复合物（NPC）机制正在成为维持基因组完整性和对DNA双链断裂（DSB）诱导剂（如电离辐射（IR））敏感性的重要决定因素。在这项研究中，使用高通量siRNA筛选，我们确定了中央通道NPC蛋白Nup54，并伴随其分子伴侣Nup62和Nup58，作为新的因素牵连在放射敏感性。NUP54耗竭引起IR后有丝分裂灾难引起的细胞死亡增加，并且特别增强了G2期阻滞的持续时间和IR暴露时含有复制DNA的细胞的放射敏感性。Nup54缺失的细胞也表现出由复制DNA引起的染色体畸变的形成增加。有趣的是，我们发现Nup54与同源重组（HR）因子Rad51是上位性的。此外，使用特异性DNA损伤修复报告基因，我们观察到Nup54敲低后HR修复活性降低。与HR修复中的作用一致，我们还证明了IR后在Nup54耗尽的细胞中HR连接的DNA合成灶和姐妹染色单体交换的形成减少。我们的研究揭示了Nup54在响应IR和维持HR介导的基因组完整性中的新作用。
The nuclear pore complex (NPC) machinery is emerging as an important determinant in the maintenance of genome integrity and sensitivity to DNA double-strand break (DSB)-inducing agents, such as ionising radiation (IR). In this study, using a high-throughput siRNA screen, we identified the central channel NPC protein Nup54, and concomitantly its molecular partners Nup62 and Nup58, as novel factors implicated in radiosensitivity. Nup54 depletion caused an increase in cell death by mitotic catastrophe after IR, and specifically enhanced both the duration of the G2 arrest and the radiosensitivity of cells that contained replicated DNA at the time of IR exposure. Nup54-depleted cells also exhibited increased formation of chromosome aberrations arisen from replicated DNA. Interestingly, we found that Nup54 is epistatic with the homologous recombination (HR) factor Rad51. Moreover, using specific DNA damage repair reporters, we observed a decreased HR repair activity upon Nup54 knockdown. In agreement with a role in HR repair, we also demonstrated a decreased formation of HR-linked DNA synthesis foci and sister chromatid exchanges after IR in cells depleted of Nup54. Our study reveals a novel role for Nup54 in the response to IR and the maintenance of HR-mediated genome integrity.
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影响因子：
3.2
作者：
Freudenreich CH;Su XA
通讯作者：
Su XA
影响因子：
14.9
作者：
Ahrabi S;Sarkar S;Pfister SX;Pirovano G;Higgins GS;Porter AC;Humphrey TC
通讯作者：
Humphrey TC
影响因子：
10.5
作者：
Horigome C;Bustard DE;Marcomini I;Delgoshaie N;Tsai-Pflugfelder M;Cobb JA;Gasser SM
通讯作者：
Gasser SM
影响因子：
4
作者：
Duheron, Vincent;Nilles, Nadine;Fahrenkrog, Birthe
通讯作者：
Fahrenkrog, Birthe
影响因子：
30.8
作者：
Bennett, CB;Lewis, LK;Resnick, MA
通讯作者：
Resnick, MA