Initiation of bacteriophage T4 DNA replication and replication fork dynamics: a review in the Virology Journal series on bacteriophage T4 and its relatives

Studies during the last 15 years have provided strong evidence that T4 DNA replication initiates from specialized structures, namely R-loops for origin-dependent replication and D-loops for recombination-dependent replication (RDR). The roles of many of the T4 replication and recombination proteins in these processes are now understood in detail, and the transition from origin-dependent replication to RDR has been ascribed to both down-regulation of origin transcripts and activation of the UvsW helicase, which unwinds origin R-loops.One of the interesting themes that emerged in studies of T4 DNA metabolism is the extensive overlap between different modes of replication initiation and the processes of DNA repair, recombination, and replication fork restart. As discussed in more detail below, the distinction between origin-dependent and recombination-dependent replication is blurred by the involvement of recombination proteins in certain aspects of origin replication. Another example of overlap is the finding that repair of double-strand breaks (DSBs) in phage T4 infections occurs by a mechanism that is very closely related to the process of RDR. The close interconnections between recombination and replication are not unique to phage T4 - it has become obvious that the process of homologous recombination and particular recombination proteins play critical roles in cellular DNA replication and the maintenance of genomic stability [1-4].Most chromosomes that have been studied include defined loci where DNA synthesis is initiated. Such origins of replication have unique physical attributes that contribute to the assembly of processive replisomes, facilitate biochemical transactions by the replisome proteins to initiate DNA synthesis, and serve as key sites for the regulation of replication timing. While the actual determinants of origin activity remain ill defined in many systems, all origins must somehow promote the priming of DNA synthesis. Bacteriophage T4 contains se