In de novo purine biosynthesis (DNPS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (2.1.2.3) / inosine monophosphate cyclohydrolase (3.5.4.10) (ATIC) catalyzes the last two reactions of the pathway: conversion of 5-aminoimidazole-4-carboxamide ribonucleotide [aka Z-nucleotide monophosphate (ZMP)] to 5-formamido-4-imidazolecarboxamide ribonucleotide (FAICAR) then to inosine monophosphate (IMP). ZMP is an adenosine monophosphate (AMP) mimetic and a known activator of AMP-activated protein kinase (AMPK). Recently, a HeLa cell line null mutant for ATIC was constructed via CRISPR-Cas9 mutagenesis. This mutant, crATIC, accumulates ZMP during purine starvation. Given that the mutant can accumulate ZMP in the absence of treatment with exogenous compounds, crATIC is likely an important cellular model for DNPS inactivation and ZMP accumulation. In the current study, we characterize the crATIC transcriptome versus the HeLa transcriptome in purine-supplemented and purine-depleted growth conditions. We report and discuss transcriptome changes with particular relevance to Alzheimers disease and in genes relevant to lipid and fatty acid synthesis, neurodevelopment, embryogenesis, cell cycle maintenance and progression, extracellular matrix, immune function, TGFbeta and other cellular processes.

中文翻译：

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CRISPR-Cas9 crATIC HeLa转录组：表征ATIC缺乏和ZMP积累的新型细胞模型

在从头进行嘌呤生物合成（DNPS）中，5-氨基咪唑-4-羧酰胺核糖核苷酸甲酰基转移酶（2.1.2.3）/肌苷单磷酸环水解酶（3.5.4.10）（ATIC）催化该途径的最后两个反应：5-氨基咪唑-的转化将4-羧酰胺核糖核苷酸[aka Z-核苷酸一磷酸（ZMP）]合成为5-甲酰胺基-4-咪唑羧酰胺核糖核苷酸（FAICAR），然后合成为肌苷一磷酸（IMP）。ZMP是单磷酸腺苷（AMP）的模拟物，并且是AMP激活的蛋白激酶（AMPK）的已知激活剂。最近，通过CRISPR-Cas9诱变构建了ATIC的HeLa细胞系无效突变体。该突变体crATIC在嘌呤饥饿期间积累ZMP。假设该突变体可以在不使用外源化合物治疗的情况下积累ZMP，crATIC可能是DNPS失活和ZMP积累的重要细胞模型。在当前的研究中，我们表征了在补充嘌呤和耗尽嘌呤的生长条件下crATIC转录组与HeLa转录组的关系。我们报告和讨论转录组变化与阿尔茨海默氏病和与脂质和脂肪酸合成，神经发育，胚胎发生，细胞周期维持和进展，细胞外基质，免疫功能，TGFbeta和其他细胞过程有关的基因特别相关。