PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage.
PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage.
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DOI：
10.1093/nar/gkt835
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发表时间：
2014-01
影响因子：
14.9
通讯作者：
Caldecott KW
中科院分区：
文献类型：
--
作者：
Rulten SL;Rotheray A;Green RL;Grundy GJ;Moore DA;Gómez-Herreros F;Hafezparast M;Caldecott KW
肌萎缩侧索硬化症(ALS)与运动神经元进行性变性有关。与这种疾病相关的几个基因编码与RNA加工有关的蛋白质，包括融合肉瘤/移位肉瘤(FUS/TLS)。FUS是异质性核核糖核蛋白(HnRNP)家族的成员，它结合了数千个前-mRNAs，并可以调节它们的剪接。在这里，我们研究了FUS也是细胞对DNA损伤反应的一个组成部分的可能性。我们发现GFP标记的和内源性的FUS都重新定位到UVA激光诱导的DNA氧化损伤的位置，并且FUS的招募被聚(ADP-核糖)聚合酶活性的抑制剂极大地减少或消融。与此一致，我们发现重组FUS在体外直接与聚ADP-核糖结合，并且GFP标记的和内源性FUS都不能在缺乏聚ADP-核糖聚合酶-1的UVA激光损伤的部位积聚。最后，我们发现GFP-FUSR521G，含有与肌萎缩侧索硬化症相关的突变，显示出在UVA激光诱导的DNA损伤部位积累的能力降低。综上所述，这些数据表明，FUS是细胞对DNA损伤反应的一个组成部分，这种反应中的缺陷可能与ALS有关。
Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUSR521G, harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS.
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神经退行性疾病中的RNA结合蛋白：TDP-43及以后。
影响因子：
7.3
作者：
Hanson, Keith A.;Kim, Sang Hwa;Tibbetts, Randal S.
通讯作者：
Tibbetts, Randal S.
影响因子：
16
作者：
Beli, Petra;Lukashchuk, Natalia;Wagner, Sebastian A.;Weinert, Brian T.;Olsen, Jesper V.;Baskcomb, Linda;Mann, Matthias;Jackson, Stephen P.;Choudhary, Chunaram
通讯作者：
Choudhary, Chunaram
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
64.8
作者：
Ahel, Ivan;Ahel, Dragana;West, Stephen C.
通讯作者：
West, Stephen C.
影响因子：
14.9
作者：
El-Khamisy, SF;Masutani, M;Caldecott, KW
通讯作者：
Caldecott, KW