Mutations in two Escherichia coli genes, sipA and sipB, result in a specific inhibition of the growth of certain hybrid lambdoid bacteriophages, A immRI2, that have the early regulatory regions and adjacent genes from bacteriophage P22. The sipB391 mutation maps near minute 56 and exerts the strongest inhibitory effect on the growth of the hybrid phages. The sipAl mutation maps near ninute 72 and plays an auxiliary role: enhancing the action of sipB391. Such a role is not limited to sipAl, since there is a similar enhancement by the nusAl and nusE71 mutations. The Sip-imposed restriction on the growth of X immP22 phages is not observed if the phage carries a mutation in the cl gene. Perhaps this reflects the fact that the cl product regulates phage DNA replication and is a major determinant in the decision governing whether the phage takes the lytic or lysogenic pathway. Consistent with this idea is the observation that A immP2 DNA replication is severely inhibited in bacteria carrying the sipB391 mutation. It is suggested that sip mutations exaggerate the normal role of cl in limiting lytic growth. This causes a failure in the expression of sufficient amounts of some or all of the lytic gene products required for phage growth.Host mutants that influence the growth of lambdoid bacteriophages have served as remarkable tools both for studying the action of phage gene products and for identifying genes whose products play important roles in the physiology of the host (19). One class of host factors is those that influence phage products active in the process of establishing repressor synthesis. The hfl (high frequency of lysogeny) (4, 5; F. Banuet and I. Herskowitz, personal communication) and the him and hip (host integration mediation and host integration protein) (33,41,44) genes control the level of cII protein, a bacteriophage X protein that plays a pivotal role in the decision determining whether the infecting phage follows the lytic or lysogenic route. This regulation is exerted in three ways: (i) controlling the establishment of cI (repressor) expression (26, 56); (ii) stimulating expression of the gene int, whose product is required for prophage integration (16); and (iii) reducing expression of late genes (13,40).The cl gene of lambdoid bacteriophage P22 maps in the same relative position as the cIT gene of X and encodes a protein that serves functions analogous to those of the cII protein (35, 52). P22, whose natural host is Salmonella typhimurium, is unable to infect Escherichia coli because it is unable to adsorb. Hybrid phages that are able to grow in E. coli have been engineered under special conditions by using in vivo recombination (10, 23, 28, 58). Some of these hybrids carry the early regulatory and replication genes of P22 and the late morphogenic genes of X including those encoding tail proteins. The relevant genetic structures of X and P22 are shown in Fig. 1. The hybrids used in our experiments carry the early regulatory region from P22 (immC), which includes the c2 (repressor) gene, and t...