GUEST COMMENTARIES Bacteriophage P1 in Retrospect and in Prospect

In consenting to publish an extravagantly long report of the most tedious kind—a genome analysis (10)—this journal has shown what appears to be extraordinary indulgence. The genome is that of P1, a bacteriophage that, unlike certain of its cousins, neither raises hopes nor instills fear. P1 phage particles are not the “great hope of universal therapy and prophylaxis,” as Felix d’Hérelle believed bacteriophages that target pathogens might be (quoted in reference 14). In the more than 50 years since the discovery of P1, the phage has not been drafted for a combat role in therapy (11). As for the P1 prophage, it does not confer toxigenicity on a harmless bacterium, as do the prophages that have given us, among other troubles, diphtheria, cholera, toxic shock syndrome, and botulism (4), nor does P1 normally subvert antibiotic treatments, despite its capacity to acquire and transfer multidrug resistance genes while sacrificing nothing more than some of its extensive terminal redundancy. P1, if not a phage “of interest,” is nevertheless an interesting phage. It has long been the workhorse of gene transduction, and its packaging and recombination systems are much in use for the genetic engineering of eukaryotes. What sets P1 apart from the majority of characterized temperate phages is the autonomy of the prophage. P1 lysogenizes its hosts as a plasmid of low copy number and, because it has the viral option, can be manipulated more conveniently than other large plasmids, most of which are horizontally transmitted by conjugation without extensive amplification. But is P1 such a very important phage as to merit the royal treatment accorded the analysis of its genome? Yes, it is. P1 opens new perspectives on familiar biological topics, to one of which I shall return shortly. It also boasts a distinguished history. P1 has played a prominent role in the development of molecular biology. The experiments of Werner Arber and Daisy Dussoix (beginning with reference 1), showing P1 to be capable of conferring a phenotype on DNA, can be said to have ushered in the new biology in which restriction-modification (R-M) plays such a key role. The several contributions of P1 are widely known, and the reader can refresh his memory of them by reading the introductory section of the accompanying report (10). That gene-by-gene survey of P1 has the virtue of bringing together scattered information to give a broad picture of the phage and is the most ambitious overview of P1 to be published since 1988 (15). Although not conceived as a review of the literature, the report seeks to provide a meaningful context for the new sequence data and so offers the reader, as an alternative to casual table-hopping, the opportunity to make a more intimate acquaintance with the subject. Much more attention has been bestowed on T4 and on lambda than on P1. The only recent P1 review (9) is modest in scope. T4 is the subject of a comprehensive compendium, revised in 1994 (8), and a major recent review (12). Lambda is honored by two sequential volumes, known respectively among “lambdologists” as the “lambda bible” (7) and, with unmerited pessimism, “lambda’s tombstone” (6). A separate monograph that is largely about the lambda immunity switch is a movie script awaiting a Fellini (13). Simulators are finding the socalled “genetic switch” irresistible (2), and a movie of the simulacra, if not by a famous director, is sure to come. For the record, lambda has no genetic switch; the one so named is epigenetic. P1, on the other hand, does possess a genetic switch, and it is used for exchanging specificity elements on delicate appendages that laboratory strains of lambda appear to have lost, tail fibers. Knowledge of P1 is not as extensive as knowledge of T4 or lambda, but in some respects, it is not far behind. The R-M system of P1, although overshadowed by the subsequently discovered type II R-M systems, has been thoroughly studied. Genes required for plasmid maintenance, including the complex immunity system of P1, have been analyzed in detail, and the critical DNA regions were sequenced several years ago. On the other hand, large regions of P1 remained unsequenced until now. Relatively little is known about morphogenesis of the virion beyond the evidence obtained from early genetic and electron micrographic studies. The present analysis fills a number of obvious gaps, albeit with several tentative and imprecise assignments of genes to structural, regulatory, and enzymatic functions. Probably the most useful function of the genome analysis is to make a larger public aware that our present understanding of P1 raises questions of general interest, some that deserve revival and some that could not have been asked before. The absence, until now, of any broad review on P1 in a widely circulated journal means that much that is known about the phage has not been given the attention deserved. There are exceptions. Notice is being taken of how efficiently P1 breaks free from the confines of its host, and P1 partitioning genes are finally creating a flurry of interest as the curtain rises on the blurry ballet (with glowing tutus courtesy of Aequorea victoria). Other topics, unaided by the appeal of liberation or of false color, have fallen into benign neglect; the P1 immunity circuitry is an obvious case in point. The relevant genes are located in three separate regions: ImmC, ImmI, and ImmT (Fig. 1). In ImmC is the c1 master * Mailing address: Laboratory of Biochemistry, National Cancer Institute, NIH, 37 Convent Dr., Bethesda, MD 20892-4255. Phone: (301) 496-5226. Fax: (301) 402-3095. E-mail: [email protected].