All known DNA polymerases are unable to initiate synthesis of a DNA strand without a preexisting "primer" sequence. Circular genomes overcome this limitation fairly easily, either by nicking one strand and using the exposed 3' end as a primer or by opening the duplex at an origin, starting with an RNA primer, and then replicating around the circle back to the starting point. The original RNA can be removed by DNA polymerase I via nick translation because the newly replicated strand returns back to the origin.

Not all genomes, however, are circular. Numerous linear genomes exist, including eukaryotic chromosomes, some bacteriophages, and some viruses. Full replication of linear genomes is a logistical problem (Figure 24.40), however, because a primer is needed for DNA polymerase. With circular chomomosomes, RNA primers can be easily removed and replaced because the newly synthesized strand returns to the origin and can serve as a primer for DNA polymerase I to replace the ribonucleotides of the RNA primer with deoxyribonucleotides. There is no loss of nucleotides in this process.

If linear chromosomes employ RNA to initiate replication at the chromosomal termini, either they must have some mechanism for replacing the RNA with DNA or they must lose a bit of DNA with each round of replication. In reality, eukaryotic chromosomes opt for the latter scheme, losing a bit of the end of each chromosome (called a telomere) with each round of replication. Telomeres contain many repeats of a small oligonucleotide sequence and do not appear to code for any genes. The enzyme called telomerase can rebuild telomeres that have been shortened, to some extent, but it does not appear to be active in most cells. Fortunately, telomeric sequences are fairly long, so our cells can undergo a considerable amount of replication without loss of important coding sequences.

Viruses with linear DNA sequences have come up with a variety of mechanisms for fully replicating the ends of their chromosome. Two of these are depicted in Figure 24.41..

Bacteriophages T4 and T7 contain terminally redundant DNA sequences that, in single-stranded form, can create concatemers (Figure 24.41a, Step3) that regenerate full terminal repeat sequences by recombination.

Bacteriophage 29 and the adenoviruses employ a completely different strategy (Figure 24.41b). They solve the problem by using a novel priming system that employs a protein covalently attached to the 5'-most nucleotide of each strand. In this case, there is no RNA that has to be removed because the terminal nucleotide that initiates the replication is a deoxyribonucleotide.

Poxviruses solve the problem in yet another way (Figure 24.41c). The two strands of their linear genome are covalently linked together. Bidirectional replication generates the duplex intermediate (step 3) and dual strand cutting and rearrangement regenerates the original structure.