The invasion of self-splicing introns and inteins by endonuclease genes appears to have occurred multiple times, given that these elements encode endonucleases of different families and that some endonuclease genes of the same family emanate from different positions of group I introns. It appears that some of these endonucleases then adapted to function in other process-
es, e.g., repression of transcription (Van Roey and Derbyshire, this Vol.), and promotion of splicing through acquisition of maturase activity (Caprara and Waring, this Vol.).
Inteins share an ancestry with metazoan hedgehog proteins, which undergo a self-cleavage reaction. The common Hint (hedgehog/intein) domain is a structural unit with a mechanistic identity (Dassa and Pietrokovski, this Vol.). It is apparent that composite elements like mobile introns, inteins and hedgehog proteins have interchanged functional domains in the course of evolution.
Endonucleases themselves have evolved specificity by fusion of a catalytic domain, containing the conserved motif, with variant DNA-binding domains, e.g., the GIY-YIG and HNH endonucleases (Van Roey and Derbyshire, this Vol.). The modular nature of these enzymes is further illustrated for I-TevI, in which the DNA-binding domain is itself an assembly of small DNA-binding units, some of which are present in other homing endonucleases. These enzymes have evolved a broad range of binding specificities, through the shuffling of catalytic cartridges with DNA-binding cassettes. We can only speculate as to how such molecular mosaics are formed. The most popular view is that proposed for hybrid bacteriophage genomes, in which "illegitimate recombination takes place quasi-randomly along the recombining genomes, generating an unholy mélange of recombinant types" (Pedulla et al. 2003). This sloppy, non-homologous recombination would generate a mound of genetic junk, with only a miniscule number of recombinants being selected, on the basis of their function and/or viability.
A lingering question is whether homing endonucleases and their genes are maintained specifically to promote their own selfish lifestyles and that of their host elements (introns and inteins), or whether they additionally serve some useful function for the organism. While their invasiveness and success as selfish intruders are undisputed, a potential advantage to the host organism has been observed, in experiments with phage T4 and its relative T2 (Edg-ell, this Vol.). Here, GIY-YIG homing endonucleases act to promote the spread of genes from their host organism to its relatives. This is a satisfying observation, considering that 8% of the phage T4 genome comprises endonuclease genes. Another "useful" homing enzyme is HO endonuclease, the first member of the LAGLIDADG family to be discovered, and the first shown to make a DSB. This intriguing enzyme catalyzes mating-type switching in yeast (Haber and Wolfe, this Vol.).
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