The clustered regularly interspaced short palindromic repeats (CRISPR) system and the CRISPR-associated proteins (Cas) make up an adaptive immune mechanism used by many bacteria and archaea to protect themselves from invading genetic material. Despite the immense evolutionary advantage of the CRISPR-Cas system, it must be meticulously regulated as it has the potential to target endogenous genes and damage the host organism. Identifying the main regulators involved in this process and how they are influenced by distinct conditions are of great clinical interest, since this prokaryotic defense system can be exploited for genome editing and therapy development. This review aims to elucidate the regulation of the CRISPR system in bacterial communities—upon quorum sensing and alginate production in biofilms—and in stressed conditions—upon antibiotic treatment or induction of the Rcs response. Despite the intrinsic contradictions of the results gathered in this review, growth rate is identified as a potential unifying regulator of CRISPR immunity. Overall, the regulation of the CRISPR-Cas system is shown to be multi-dimensional and cross-sectional, to greatly vary amongst lineages, and to be highly sensitive to conditional changes.
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