Discovery of Oligonucleotide Signaling Mediated by CRISPR-Associated Polymerases Solves Two Puzzles but Leaves an Enigma
Discovery of Oligonucleotide Signaling Mediated by CRISPR-Associated Polymerases Solves Two Puzzles but Leaves an Enigma
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DOI：
10.1021/acschembio.7b00713
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发表时间：
2018-02-01
影响因子：
4
通讯作者：
Makarova, Kira S.
中科院分区：
文献类型：
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作者：
Koonin, Eugene V.;Makarova, Kira S.
III型CRISPR-Cas系统的特征组分是Cas 10蛋白，其由与DNA和RNA聚合酶和核苷酸环化酶的结构域同源的两个Palm结构域和HD核酸酶结构域组成。然而，直到最近，Palm结构域的活性及其在CRISPR功能中的作用尚未通过实验确定。大多数III型CRISPR-Cas系统和一些I型系统还包括含有CARF（CRISPR相关罗斯曼折叠）结构域的蛋白质，该结构域已被预测通过核苷酸结合来调节CRISPR功能，但其在CRISPR-Cas中的功能仍然不清楚。最近的两项独立研究表明，Cas 10的Palm结构域催化寡聚腺苷酸的合成，寡聚腺苷酸结合Csm 6蛋白的CARF结构域并激活其RNase结构域，该结构域切割外源转录物，从而实现III型CRISPR-Cas的干扰。在一次政变中，这些发现解决了CRISPR生物学的两个长期难题，并揭示了控制CRISPR反应的新调控途径。然而，这一途径的全部范围，特别是这种复杂的CRISPR-Cas激活机制演变背后的驱动力，仍有待发现。
The signature component of type III CRISPR-Cas systems is the Cas10 protein that consists of two Palm domains homologous to those of DNA and RNA polymerases and nucleotide cyclases and an HD nuclease domain. However, until very recently, the activity of the Palm domains and their role in CRISPR function have not been experimentally established. Most of the type III CRISPR-Cas systems and some type I systems also encompass proteins containing the CARF (CRISPR-associated Rossmann fold) domain that has been predicted to regulate CRISPR functions via nucleotide binding, but its function in CRISPR-Cas remained obscure. Two independent recent studies show that the Palm domain of Cas10 catalyzes synthesis of oligoadenylates, which bind the CARF domain of the Csm6 protein and activate its RNase domain that cleaves foreign transcripts enabling interference by type III CRISPR-Cas. In one coup, these findings resolved two long-standing puzzles of CRISPR biology and reveal a new regulatory pathway that governs the CRISPR response. However, the full extent of this pathway, and especially the driving forces behind the evolution of this complex mechanism of CRISPR-Cas activation, remains to be uncovered.