Many small replicons that have circular genomes such as circular ssDNA viruses and circular plasmids replicate via rolling circle replication (RCR), which is a unidirectional, strand displacement form of DNA replication similar to RHR. In RCR, successive rounds of replication, which proceeds in a loop around the genome, are initiated and terminated by site-specific single-strand nicks made by a replicon-encoded endonuclease, variously called the nickase, relaxase, mobilization protein (mob), transesterase, or replication protein (Rep). The replication initiator protein of parvoviruses is genetically related to these other endonucleases.
RCR initiator proteins contain three motifs considered to be important for replication. Two of these are retained within parvovirus initiator proteins: an HUHUUU cluster, which is presumed to bind to a  ion required for nicking, and a YxxxK motif that contains the active-site tyrosine residue that attacks the phosphodiester bond of target DNA. In contrast to RCR initiator proteins, which can join together DNA strands, RHR initiator proteins have only vestigial traces of being able to perform ligation.
RCR begins when the initiator protein nicks a DNA strand at a specific sequence in the replication origin region. This is done through a transesterification reaction that forms a 5′-phosphate bond that connects the DNA to the active-site tyrosine and frees the 3′-end hydroxyl (3′-OH) adjacent to the nick site. The 3′-end is then used as a primer for the host DNA polymerase to begin replication while the initiator protein remains attached to the 5′-end of the "original" strand. After one loop of replication around the circular genome, the initiator protein returns to the nick site, i.e. the original initiator complex, while still attached to the parent strand and attacks the regenerated duplex nick site, or a nearby second site in some cases, by means of a topoisomerase-like nicking-joining reaction.
During the aforementioned reaction, the initiator protein cleaves a new nick site and is transferred across the analogous phosphodiester bond. It thereby becomes attached to the new 5′-end while ligating the 5′-end of the first strand to which it was originally attached to the 3′-end of the same strand. This second mechanism varies depending on the replicon. Some replicons such as the virus ΦX174 contain a second active tyrosine residue in the initiator protein. Others use the analogous active-site tyrosine in a second initiator protein that is present as part of a multimeric nickase complex.
This second nicking reaction may occur after one loop or successive loops may occur in which a concatemer containing multiple copies of the genome is created. The result of this nick is that displaced genomes become detached from the replicative molecule. These copies of the genome are ligated and may either be encapsidated into progeny capsids, provided they are monomeric, or converted to a covalently-closed double-stranded form by a host DNA polymerase for further replication. While RHR generally involves replication of both sense strands in a continuous process, RCR has complementary strand synthesis and genomic strand synthesis occur separately.
The strategies used in RHR to engage the nick site are also present in RCR. Most RCR origins are in the form of duplex DNA that has to be melted before nicking. RCR initiators accomplish this by binding to specific DNA-binding sequences in the origin next to the initiation site. The latter site is then melted in a process that consumes ATP and which is assisted by the ability of the separated strands to reconfigure into stem-loop structures. In these structures, the nick site is presented on an exposed loop. Like RHR initiator proteins, many RCR initiator proteins contain helicase activity, which allows them to melt the DNA prior to nicking and serve as the 3′-to-5′ helicase in the replication fork.