In prokaryotes, CRISPR-Cas immune systems recognize and cleave foreign nucleic acids to defend against mobile genetic elements (MGEs). Type III CRISPR-Cas complexes also synthesize cyclic oligoadenylate (cOA) second messengers, which activate CRISPR ancillary proteins involved in antiviral defense. In particular, cOA-stimulated nucleases degrade RNA and DNA nonspecifically, which slows MGE replication but also impedes cell growth, necessitating mechanisms to eliminate cOA in order to facilitate cell recovery. Extant cOA is degraded by a new class of enzyme termed a “ring nuclease,” which cleaves cOA specifically and switches off CRISPR ancillary enzymes. Several ring nuclease families have been characterized to date, including a family used by MGEs to circumvent CRISPR immunity, and encompass diverse protein folds and distinct cOA cleavage mechanisms. In this review we examine cOA signaling, discuss how different ring nucleases regulate the cOA signaling pathway, and reflect on parallels between cyclic nucleotide-based immune systems to reveal new areas for exploration.

中文翻译：

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III型CRISPR防御过程中环状核酸酶的环状寡腺苷酸信号传导和调节

在原核生物中，CRISPR-Cas 免疫系统识别并切割外来核酸以抵御移动遗传元件 (MGE)。III 型 CRISPR-Cas 复合物还合成环状寡腺苷酸 (cOA) 第二信使，可激活参与抗病毒防御的 CRISPR 辅助蛋白。特别是，cOA 刺激的核酸酶非特异性地降解 RNA 和 DNA，这会减慢 MGE 复制但也会阻碍细胞生长，因此需要消除 cOA 以促进细胞恢复的机制。现存的 cOA 被称为“环状核酸酶”的一类新酶降解，该酶特异性地裂解 cOA 并关闭 CRISPR 辅助酶。迄今为止，已经表征了几个环状核酸酶家族，包括 MGE 用来规避 CRISPR 免疫的家族，并包含不同的蛋白质折叠和不同的 cOA 切割机制。在这篇综述中，我们检查了 cOA 信号，讨论了不同的环核酸酶如何调节 cOA 信号通路，并反思基于环核苷酸的免疫系统之间的相似之处，以揭示新的探索领域。