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The mechanisms used for momentarily functionally uncoupling synthesis of the two strands differ depending on whether the lesion occurs on the leading-strand or lagging-strand template. The discontinuous nature of replication on the lagging-strand template affords the opportunity to circumvent lesions that halt DNA polymerase III. Typically, DNA polymerase III is recycled onto a new DNA primer when a new RNA primer is deposited (Figure 1.10). However, a stalled lagging-strand DNA polymerase III can also be recycled by premature release when it stalls at DNA damage (Figure 1.13A). The single-strand DNA gap left behind is repaired by another mechanism.

Under the historical model of the function of DnaG primase, primers are placed only on the lagging-strand template. However, biochemical studies indicate that in cases where the leading-strand polymerase stalls, primase can also produce an RNA primer on the leading-strand template, allowing replication to continue but leaving a gap on this strand (Figure 1.13B). This process of lesion skipping on the leading-strand template and the ability to utilize alternative polymerases (described below) to copy over DNA damage provide complementary mechanisms to deal with damaged DNA template strands (see Gabbai et al., Suggested Reading).

While DNA polymerase III and DNA polymerase I are important for high-fidelity DNA replication, other DNA polymerases are found in E. coli that allow replication through damaged DNA in a process known as translesion synthesis. Most translesion polymerases appear to come with a trade-off in which the ability to copy damaged DNA results in a lower fidelity of DNA replication. As expected, the expression of these polymerases is induced as a response to DNA damage in the cell. In addition to controlling the amount of translesion polymerase present in the cell, access to the DNA replication fork by polymerases other than DNA polymerase III is regulated by a process called polymerase switching, a process by which one DNA polymerase replaces a polymerase already found at the 3′ OH end of a primed DNA template (Figure 1.13C). In E. coli, DNA polymerases II, IV, and V can be recruited to temporarily step in for DNA polymerase III at damaged DNA (more details of this system are described in chapter 10). Each of these polymerases has different attributes, ranging from fairly accurate and highly processive (DNA polymerase II) to very inaccurate and not very processive (DNA polymerases IV and V). Processivity refers to how far a DNA polymerase moves on the template before falling off.

Having multiple DNA polymerases with different properties appears to be common in all living organisms. How accurate or processive a given DNA polymerase is may also depend on the nature of the damage found in the template DNA and/or the availability of various accessory proteins. The regulation of the use of these DNA polymerases is still incompletely understood, but there appear to be highly evolved processes in which the system has been fine-tuned by the process of natural selection over a long time so that the most appropriate DNA-copying mechanism is used for each environmental challenge.