Intein-splicing can control archaeal DNA replication

Inteins, or intervening proteins, are mobile genetic elements removed from host proteins following translation through a self-mediated splicing reaction. Inteins are abundant in the microbial world, found within nearly one-quarter of Bacteria and one-half of Archaea, often clustering within essential genes involved in DNA replication, recombination, and repair. The strong bias of inteins encoded within non-orthologous replisome components argues that conditional intein excision - controlled by environmental signals - might regulate the concentration of matured, active (e.g. intein-free) replisome components and thus replication activities in vivo. Here we show that the efficiency of intein excision from the essential RadA recombinase changes the concentration of functional RadA in vivo which ultimately drives a foundational switch between recombination-dependent and origin-dependent DNA replication in the archaeon Thermococcus kodakarensis. Our findings demonstrate the long-hypothesized and impactful regulatory potential of intein splicing in a natural intein-containing host and support that some inteins have been exaptated from parasitic- to important regulatory- elements . How intein splicing - perhaps the most radical form of post-translational protein modification - may be regulated by the environment, how changes in the efficiency of splicing alter microbial physiology, and may limit the growth of pathogens, are now questions with an in vivo basis.