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Type III CRISPR‐Cas systems are based on the Cascade‐like complexes (Csm or Cmr in subtypes III‐A and III‐B, respectively) working with their cognate hairpinless crRNAs. These complexes display overall structural similarity to Cascade complex of type I, both forming a seahorse‐shaped complex (Osawa et al. 2015; Taylor et al. 2015). In the Csm/Cmr complex, the 5’ end of the crRNA is bound by Cas5, with the backbone of multiple proteins belonging to Cas7 (Csm3/Csm5 and Cmr4/Cmr6/Cmr1) and Cas11 (Csm2/Cmr5) protein families. The effector complex is completed by binding of Cas10 protein (Figure 3.4b). The distinct feature of type III systems is that they can degrade both DNA and RNA, through concerted DNase activity of Cas10 and RNase activities of Csm3 and ancillary Csm6 proteins (Hale et al. 2009; Deng et al. 2013; Staals et al. 2014; Samai et al. 2015).

Type III systems confer immunity against DNA bacteriophages or plasmids (Marraffini and Sontheimer 2008; Hatoum‐Aslan et al. 2014; Samai et al. 2015), but can only target the invading genome if it is actively transcribed (Deng et al. 2013; Goldberg et al. 2014). Whether Csm/Cmr complexes get recruited directly to transcribing RNA polymerase, nascent transcript, or underwound DNA generated in the wake of RNA polymerase remains a contentious topic (Elmore et al. 2016; Han et al. 2017; Liu et al. 2019b). It is clear that interference begins by the pairing of loaded crRNA to complementary nascent transcript (Figure 3.4b), stimulating the nucleolytic degradation of the nontarget DNA strand by Cas10 (Estrella et al. 2016; Liu et al. 2017d). In parallel, Cas7 subunits cleave the paired RNA at every sixth nucleotide (Tamulaitis et al. 2014; Liu et al. 2017d), and in some systems the ancillary RNase Csm6 degrades proximal RNA in an unspecific manner (Jiang et al. 2016b); this dual action of two main nucleases efficiently silences phage RNA and simultaneously disrupts the invasive genome (Figure 3.4b). Type III‐A system have evolved even stronger adaptive response, where targeted binding to RNA stimulates unspecific cleavage of ssDNA by the HD domain of Cas10 (Kazlauskiene et al. 2016; Liu et al. 2017d), and the conversion of ATP to cycling oligoadenylates by its Palm polymerase domain. The cyclic oligoadenylates further stimulate the activity of the HEPN domain of the Csm6 ribonuclease (Kazlauskiene et al. 2017; Niewoehner et al. 2017), leading to an indiscriminate degradation of both host and invading RNA, causing a growth arrest which restricts invader propagation (Jiang et al. 2016b; Rostol and Marraffini 2019). Together, this gives rise to a potent, highly adaptable, and robust immune system (Pyenson et al. 2017).