Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
RNA. 2012 Oct;18(10):1833-45. doi: 10.1261/rna.034942.112. Epub 2012 Aug 24.
The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes.
AAA+ ATP 酶 pontin 和 reptin 参与了一系列令人瞩目的细胞过程，包括染色质重塑、转录调控、DNA 损伤修复以及大分子复合物的组装，如 RNA 聚合酶 II 和小核仁（sno）RNPs。然而，所有这些 AAA+ ATP 酶相关活性的分子机制尚不清楚。在这里，我们记录了在 H/ACA RNPs（包括端粒酶）的生物发生过程中，组装因子 SHQ1 以一种类似夹具的方式将假尿嘧啶合酶 NAP57/dyskerin 固定住，并且 pontin 和 reptin（作为 R2TP 复合物的组成部分）需要将 NAP57 从 SHQ1 上撬下来。重要的是，被 SHQ1 捕获的 NAP57 结构域包含大多数导致 X 连锁先天性角化不良症（X-DC）的突变，这表明这两种蛋白质之间的界面是骨髓衰竭综合征的一个靶点。针对 H/ACA RNP 生物发生的基本步骤，我们的发现首次提供了 pontin 和 reptin 在大分子复合物组装中的作用机制的见解。
