Parusel Christine T, Kritikou Ekaterini A, Hengartner Michael O, Krek Wilhelm, Gotta Monica
Eidgenoessische Technische Hochschule Zuerich, Institute of Cell Biology, CH-8093 Zuerich, Switzerland.
Development. 2006 Feb;133(4):621-9. doi: 10.1242/dev.02235.
Unconventional prefoldin RPB5 interactor (URI), an evolutionary conserved member of the prefoldin family of molecular chaperones, plays a central role in the regulation of nutrient-sensitive, TOR (target-of-rapamycin)-dependent gene expression programs in yeast. Mammalian URI has been shown to associate with key components of the transcriptional machinery, including RPB5, a shared subunit of all three RNA polymerases, the ATPases TIP48 and TIP49, which are present in various chromatin remodeling complexes, and human PAF1 and parafibromin, which are components of a transcription elongation complex. Here, we provide the first functional characterization of a URI-1 homolog in a multicellular organism and show that the C. elegans gene uri-1 is essential for germ cell proliferation. URI-1-deficient cells exhibit cell cycle arrest and display DNA breaks as evidenced by TUNEL staining and the appearance of HUS-1::GFP foci formation. In addition, uri-1(lf) mutants and uri-1(RNAi) worms show a p53-dependent increase in germline apoptosis. Our findings indicate that URI-1 has an important function in the mitotic and meiotic cell cycles. Furthermore, they imply that URI-1 participates in a pathway(s) that is associated with the suppression of endogenous genotoxic DNA damage and highlight a role for URI-1 in the control of genome integrity.
非常规预折叠蛋白RPB5相互作用因子（URI）是分子伴侣预折叠蛋白家族中进化保守的成员，在酵母中对营养敏感的、雷帕霉素靶蛋白（TOR）依赖性基因表达程序的调控中起核心作用。哺乳动物的URI已被证明与转录机制的关键成分相关，包括RPB5（所有三种RNA聚合酶的共享亚基）、存在于各种染色质重塑复合物中的ATP酶TIP48和TIP49，以及作为转录延伸复合物成分的人类PAF1和副纤维蛋白。在这里，我们首次对多细胞生物中的URI-1同源物进行了功能表征，并表明秀丽隐杆线虫基因uri-1对生殖细胞增殖至关重要。URI-1缺陷细胞表现出细胞周期停滞，并显示出DNA断裂，TUNEL染色以及HUS-1::GFP焦点形成的出现证明了这一点。此外，uri-1（lf）突变体和uri-1（RNAi）蠕虫显示出种系凋亡中p53依赖性增加。我们的研究结果表明，URI-1在有丝分裂和减数分裂细胞周期中具有重要功能。此外，它们暗示URI-1参与了与内源性基因毒性DNA损伤抑制相关的途径，并突出了URI-1在基因组完整性控制中的作用。
