Restriction-Modification Systems as Minimal Forms of Life

A restriction (R) endonuclease recognizes a specific DNA sequence and introduces a double-strand break (Fig. 1A). A cognate modification (M) enzyme methylates the same sequence and thereby protects it from cleavage. Together, these two enzymes form a restriction-modification system. The genes encoding the restriction endonuclease and the cognate modification enzyme are often tightly linked and can be termed a restriction-modification gene complex. Restriction enzymes will cleave incoming DNA if it has not been modified by a cognate or another appropriate methyltransferase (Fig. 1B). Consequently, it is widely believed that restriction-modification systems have been maintained by bacteria because they serve to defend the cells from infection by viral, plasmid, and other foreign DNAs (cellular defense hypothesis). An alternative hypothesis for the maintenance of restriction-modification systems is based on the observation that several restriction-modification gene complexes in bacteria are not easily replaced by competitor genetic elements because their loss leads to cell death (post-segregational killing; Naito et al. 1995; Handa et al. 2001; Sadykov et al. 2003; Figs. 1C, 2B). This finding led to the proposal that these complexes may actually represent one of the simplest forms of life, similar to viruses, transposons, and homing endonucleases. This selfish gene hypothesis (Naito et al. 1995; Kusano et al. 1995; Kobayashi 1996, 1998, 2001) is now supported by many lines of evidence from genome analysis and experimentation. A third type of hypothesis that explains why restriction-modification systems are present assumes that they aid the generation of diversity (Arber 1993; Price and Bickle 1986; variation hypothesis). Supporting this notion is that these systems are indeed associated with genome variation in a number of different ways (Sect. 2). However, such restriction-modification-associated