Abstract
Rolling circle replication (RCR) is ubiquitously used by cellular and viral systems for genome and plasmid replication. While the molecular mechanism of RCR has been described, the structural mechanism is desperately lacking. Circular-rep encoded single stranded DNA (CRESS-DNA) viruses employ a viral encoded replicase (Rep) to initiate RCR. The recently identified prokaryotic homologues of Reps may also be responsible for initiating RCR. Reps are composed of an endonuclease, oligomerization, and ATPase domain. Recent structural studies have provided structures for all these domains such that an overall mechanism of RCR initiation can begin to be synthesized. However, structures of Rep in complex with its various DNA substrates and/or ligands are lacking. Here we provide a 3D bioinformatic review of the current structural information available for Reps. We combine an excess of 1590 sequences with experimental and predicted structural data from 22 CRESS-DNA groups to identify similarities and differences between Reps that lead to potentially important functional sites. Experimental studies of these sites may shed light on how Reps execute their functions. Furthermore, we identify Rep-substrate or Rep-ligand structures that are urgently needed to better understand the structural mechanism of RCR.
Highlights
Viruses 2022, 14, 37. https://doi.org/Rolling-circle replication (RCR) was introduced by Gilbert and Dressler more than half a century ago to describe the molecular mechanism of genome replication by the bacteriophage φX174 [1]
What is the diversity of primary structure within each of the 23 groups identified by Kazlauskas et al, and do the groups demonstrate comparable diversity? We attained a total of 1595 unique sequences, and each sequence could be assigned to one of the 22 groups defined by Kazlauskas et al
More than half a century ago Gilbert and Dressler described the molecular mechanism of genome replication by bacteriophage φX174 as Rolling circle replication (RCR) [1]
Summary
Rolling-circle replication (RCR) was introduced by Gilbert and Dressler more than half a century ago to describe the molecular mechanism of genome replication by the bacteriophage φX174 [1]. RCR was used to describe replication of bacterial plasmid pT181 [2,3]. The use of RCR by viral/phage, prokaryotic plasmids, and eukaryotic transposons has become well documented [4–14]. One such system is the replication of viruses with circular single stranded DNA (ssDNA) genomes. While these studies have provided the molecular mechanism describing RCR, structural detail is desperately lacking. RCR begins with an initiator protein binding to a sequence specific origin of replication (ori) located on the double stranded DNA (dsDNA). According to the number of functional domains they possess, initiator proteins can be categorized into two groups: (1) the pT181-like group, and (2) the circular-rep encoded single stranded
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