The roles of CRISPR–Cas systems in adaptive immunity and beyond
Graphical abstract
Introduction
The ability to withstand viral predation is a hallmark of survival for most life forms. Over time, bacteria have managed to thrive in a diversity of inhospitable habitats, despite challenging environmental conditions, competition for scarce resources, and predation from other life forms such as viruses. Much of the sustainable success of bacteria lies in their concurrent ability to flexibly expand their genetic repertoire, dynamically manage genome homeostasis, and fend off viruses using a plethora of defense systems. Noteworthy, eubacteria have managed to control the size of their genomes by balancing tactical acquisition of beneficial material with strategic loss of extraneous and redundant genes, in a dynamically choreographed dance with invasive mobile genetic elements such as plasmids, viruses, and transposons [1]. Remarkably, bacteria have managed to orchestrate this without the genome expansion observed in the most advanced eukaryotes, in which a large proportion of the genome consists of extraneous and redundant repeated elements derived from exogenic elements. The recently discovered clustered regularly interspaced short palindromic repeats (CRISPR) and associated proteins (Cas) have been shown to provide immunity against viruses and plasmids in bacteria and archaea, in an adaptive manner, and has been established as a critical guardian of bacterial genomes [2, 3, 4]. However, several recent studies have shed light on additional functional roles of CRISPR–Cas systems, beyond immunity. These novel roles expand the functional repertoire of CRISPR–Cas systems and highlight the need to manage tradeoffs between safe-keeping genome integrity, and acquisition of beneficial mobile genetic elements for adaptive purposes.
Section snippets
CRISPR–Cas systems provide adaptive immunity in bacteria
Generally, CRISPR–Cas immune systems function in three distinct stages that provide DNA-encoded [5••], RNA-mediated [6••], sequence-specific targeting of exogenous nucleic acids [7••, 8] (Figure 1). Specifically, as part of the adaptation process, pieces of DNA are sampled from invasive mobile genetic element and acquired as novel ‘spacers’ into CRISPR loci, to build immunity and immune memory [5••]. Subsequently, during the expression process, this repeat-spacer array is transcribed and
Repurposing the Cas machinery for genome editing and transcriptional control
Notwithstanding the natural immune role of CRISPR–Cas systems in prokaryotes, the most visible and significant recent research has arguably been centered around the repurposing of the Cas machinery for genome editing and transcriptional control in eukaryotes [19, 20]. Indeed, repurposing of the programmable Cas9 endonuclease has revolutionized genome editing [21, 22, 23•] and open new avenues for transcriptional control with unprecedented ease and flexibility [24, 25, 26, 27, 28, 29], as
The evolutionary cost(s) of playing defense
Original studies investigating the immune role of CRISPR–Cas systems in bacteria and archaea have provided insights into the co-evolutionary interplay between prokaryotes and their viruses in general, and their genetic arms race in particular [12, 13, 14, 15, 32, 33, 34]. Indeed, studies have shown that CRISPR loci rapidly diversify in populations exposed to viruses [14, 17]. In response, bacteriophages rapidly evolve to specifically escape CRISPR-encoded immunity by mutating or even deleting
CRISPR roles beyond adaptive immunity
Although antiviral vaccination has been shown for various CRISPR–Cas systems, several recent studies have unraveled functions beyond adaptive immunity [43]. Actually, a growing body of work is shedding light on the costs and benefits of CRISPR–Cas systems, which has expanded our understanding of the various roles they play in bacteria. A new perspective has emerged on CRISPR functions, based on the ability to control transcription endogenously, and regulate important lifestyle-based bacterial
Perspective
Altogether, the relationship between CRISPR and their hosts can be ‘complicated’ at times, with the need to strategically balance tradeoffs between limiting susceptibility to invasive mobile genetic elements on one hand (maintaining genome integrity), and the ability to uptake valuable exogenous DNA on the other hand (allowing genome flexibility). As further studies investigate the function(s) of CRISPR–Cas systems in a variety of organisms and model systems, the extent of their role beyond
Conflicts of interest
RB is a co-inventor on several patents related to CRISPR–Cas systems and their various uses. RB is also on the board of directors of Caribou Biosciences, and a co-founder of Intellia Therapeutics.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
RB is supported by start up funds from North Carolina State University. The author would like to thank his many colleagues and collaborators in the CRISPR field for their insights into these fantastic molecular systems.
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