Evolutionary Role of Restriction/Modification Systems as Revealed by Comparative Genome Analysis

Abstract

Type II restriction modification systems (RMSs) have been regarded either as defense tools or as molecular parasites of bacteria. We extensively analyzed their evolutionary role from the study of their impact in the complete genomes of 26 bacteria and 35 phages in terms of palindrome avoidance. This analysis reveals that palindrome avoidance is not universally spread among bacterial species and that it does not correlate with taxonomic proximity. Palindrome avoidance is also not universal among bacteriophage, even when their hosts code for RMSs, and depends strongly on the genetic material of the phage. Interestingly, palindrome avoidance is intimately correlated with the infective behavior of the phage. We observe that the degree of palindrome and restriction site avoidance is significantly and consistently less important in phages than in their bacterial hosts. This result brings to the fore a larger selective load for palindrome and restriction site avoidance on the bacterial hosts than on their infecting phages. It is then consistent with a view where type II RMSs are considered as parasites possibly at the verge of mutualism. As a consequence, RMSs constitute a nontrivial third player in the host-parasite relationship between bacteria and phages.Classic type II restriction modification systems (RMSs) comprise pairs of enzymes with matching DNA sequence specificity. The modification enzyme is a DNA methyltransferase that specifically methylates either adenosyl or cytosyl residues within the recognition sequence (the restriction site; RS), thus making DNA resistant to the restriction activity. The restriction enzyme is an endodeoxyribonuclease that cleaves DNA at a precise location within or around the recognition sequence, when this sequence is not methylated (Redaschi and Bickle 1996). These recognition sequences are symmetrical, comprising 4-8 specific base pairs, and cleavage and methylation occur symmetrically within the sequences. As a consequence, foreign double stranded DNA (dsDNA), unmethylated at the restriction sites recognized by the cell's RMS, is quickly degraded.

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

“…This strategy also protects host bacteria from attack by its own REase. Interestingly, palindrome avoidance is observed to a greater extent in bacteria than in phages (84). Palindrome/restriction site avoidance by mutations, however, may affect other cellular functions.…”

“…(i) It has been observed that bacteria containing an R-M system have a decreased restriction site frequency in the genome for that particular recognition sequence, a phenomenon called restriction site avoidance (84). This strategy is employed by phages to evade restriction (see "Strategies against R-M Systems").…”

Palindromes in SARS and Other Coronaviruses

“…So far, we cannot find any previous report of underrepresentation of short palindromes in RNA viruses with eukaryotic hosts. However, avoidance of short palindromes in some bacterial and phage DNA genomes has been reported in several studies (Karlin et al 1992;Merkl and Fritz 1996;Rocha et al 1998Rocha et al , 2001, among others). The phenomenon is generally explained in relation to the defense mechanisms of the bacterial and phage genomes, protecting themselves against being destroyed by restriction enzymes capable of cutting up DNA molecules at certain palindromic sites.…”

“…Various statistical assessments of unusual abundance and rarity of individual words, including individual palindromes, in nucleotide sequences have been done using randomsequence models in a number of previous studies (Karlin et al 1992;Merkl and Fritz 1996;Rocha et al 1998Rocha et al , 2001Schbath et al 1995, to name just a few). The present study, however, aims at investigating the unusual abundance and rarity of palindromes collectively rather than individually.…”

“…Statistical and experimental studies of palindromes in the other classes of viral genomes, such as the double stranded DNA viruses, bacteriophages, retroviruses, etc., have been performed (Cain et al 2001, Dirac et al 2002, Hill et al 2003, Karlin et al 1992, Leung et al 2002, Rocha et al 2001. These studies have suggested that palindromes might be involved in the viral packaging, replication, and defense mechanisms.…”