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A potent nuclear export mechanism imposes USP16 cytoplasmic localization during interphase.
Journal of Cell Science ( IF 4 ) Pub Date : 2020-02-24 , DOI: 10.1242/jcs.239236
Nadine Sen Nkwe 1 , Salima Daou 1, 2 , Maxime Uriarte 1 , Jessica Gagnon 1, 3 , Nicholas Victor Iannantuono 1, 3 , Haithem Barbour 1 , Helen Yu 1, 4 , Louis Masclef 1 , Erlinda Fernández 1 , Natalia Zamorano Cuervo 1, 5 , Nazar Mashtalir 1, 6, 7 , Loïc Binan 1, 8 , Mikhail Sergeev 1 , François Bélanger 1 , Elliot Drobetsky 1, 9 , Eric Milot 1, 9 , Hugo Wurtele 1, 9 , Santiago Costantino 1, 8 , El Bachir Affar 9, 10
Affiliation  

Nadine Sen Nkwe, Salima Daou, Maxime Uriarte, Jessica Gagnon, Nicholas Victor Iannantuono, Haithem Barbour, Helen Yu, Louis Masclef, Erlinda Fernandez, Natalia Zamorano Cuervo, Nazar Mashtalir, Loïc Binan, Mikhail Sergeev, Francois Belanger, Elliot Drobetsky, Eric Milot, Hugo Wurtele, Santiago Costantino, and El Bachir Affar

USP16 (also known as UBP-M) has emerged as a histone H2AK119 deubiquitylase (DUB) implicated in the regulation of chromatin-associated processes and cell cycle progression. Despite this, available evidence suggests that this DUB is also present in the cytoplasm. How the nucleo-cytoplasmic transport of USP16, and hence its function, is regulated has remained elusive. Here, we show that USP16 is predominantly cytoplasmic in all cell cycle phases. We identified the nuclear export signal (NES) responsible for maintaining USP16 in the cytoplasm. We found that USP16 is only transiently retained in the nucleus following mitosis and then rapidly exported from this compartment. We also defined a non-canonical nuclear localization signal (NLS) sequence that plays a minimal role in directing USP16 into the nucleus. We further established that this DUB does not accumulate in the nucleus following DNA damage. Instead, only enforced nuclear localization of USP16 abolishes DNA double-strand break (DSB) repair, possibly due to unrestrained DUB activity. Thus, in contrast to the prevailing view, our data indicate that USP16 is actively excluded from the nucleus and that this DUB might indirectly regulate DSB repair.

This article has an associated First Person interview with the first author of the paper.



中文翻译:

有效的核输出机制在间期期间强制 USP16 细胞质定位。

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USP16(也称为 UBP-M)已成为一种组蛋白 H2AK119 去泛素化酶 (DUB),参与染色质相关过程和细胞周期进程的调节。尽管如此,现有证据表明这种 DUB 也存在于细胞质中。USP16 的核质转运及其功能是如何调节的仍然是个谜。在这里,我们表明 USP16 在所有细胞周期阶段主要位于细胞质中。我们确定了负责维持细胞质中 USP16 的核输出信号 (NES)。我们发现 USP16 在有丝分裂后仅短暂保留在细胞核中,然后迅速从该区室中输出。我们还定义了一个非规范核定位信号 (NLS) 序列,该序列在引导 USP16 进入细胞核中发挥最小作用。我们进一步确定,DNA 损伤后,这种 DUB 不会在细胞核中积累。相反,只有强制 USP16 核定位才能消除 DNA 双链断裂 (DSB) 修复,这可能是由于 DUB 活性不受限制。因此,与普遍观点相反,我们的数据表明 USP16 被主动排除在细胞核之外,并且该 DUB 可能间接调节 DSB 修复。

本文有对该论文第一作者的相关第一人称采访。

更新日期:2020-03-02
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