Strochlic Todd I, Stavrides Kevin P, Thomas Sam V, Nicolas Emmanuelle, O'Reilly Alana M, Peterson Jeffrey R
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA Epigenetics and Progenitor Cells Keystone Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
EMBO Rep. 2014 Nov;15(11):1184-91. doi: 10.15252/embr.201438688. Epub 2014 Sep 15.
The enzyme CTP synthase (CTPS) dynamically assembles into macromolecular filaments in bacteria, yeast, Drosophila, and mammalian cells, but the role of this morphological reorganization in regulating CTPS activity is controversial. During Drosophila oogenesis, CTPS filaments are transiently apparent in ovarian germline cells during a period of intense genomic endoreplication and stockpiling of ribosomal RNA. Here, we demonstrate that CTPS filaments are catalytically active and that their assembly is regulated by the non-receptor tyrosine kinase DAck, the Drosophila homologue of mammalian Ack1 (activated cdc42-associated kinase 1), which we find also localizes to CTPS filaments. Egg chambers from flies deficient in DAck or lacking DAck catalytic activity exhibit disrupted CTPS filament architecture and morphological defects that correlate with reduced fertility. Furthermore, ovaries from these flies exhibit reduced levels of total RNA, suggesting that DAck may regulate CTP synthase activity. These findings highlight an unexpected function for DAck and provide insight into a novel pathway for the developmental control of an essential metabolic pathway governing nucleotide biosynthesis.
CTP合酶（CTPS）在细菌、酵母、果蝇和哺乳动物细胞中动态组装成大分子细丝，但这种形态重组在调节CTPS活性中的作用存在争议。在果蝇卵子发生过程中，在强烈的基因组内复制和核糖体RNA储存期间，CTPS细丝在卵巢生殖系细胞中短暂出现。在这里，我们证明CTPS细丝具有催化活性，并且它们的组装受非受体酪氨酸激酶DAck调节，DAck是哺乳动物Ack1（活化的cdc42相关激酶1）的果蝇同源物，我们发现它也定位于CTPS细丝。缺乏DAck或缺乏DAck催化活性的果蝇的卵室表现出CTPS细丝结构破坏和形态缺陷，这些缺陷与生育力降低相关。此外，这些果蝇的卵巢总RNA水平降低，表明DAck可能调节CTP合酶活性。这些发现突出了DAck的意外功能，并为控制核苷酸生物合成的基本代谢途径的发育控制的新途径提供了见解。
