The Expanding Polymerase Universe
نویسندگان
چکیده
Escherichia coli DNA polymerase I (pol I), discovered by Arthur Kornberg and colleagues in 1956. Thirteen years later, Paula de Lucia and John Cairns, at Stony Brook, New York, isolated an E. coli mutant, polA (its designation being a play on de Lucia’s first name, as proposed to Cairns by Julian Gross) that seemed to have less than 1% of the normal pol I activity. From this strain, a new DNA-polymerizing enzyme, pol II, was isolated. The polA strain was much more sensitive to ultraviolet (UV) radiation than wild-type cells, suggesting that pol I might be involved in DNA repair in addition to chromosomal replication. Shortly after, using this same polA strain, Thomas Kornberg and Malcolm Gefter, and Friedrich Bonhoeffer, Heinz Schaller and colleagues, independently discovered DNA polymerase III (pol III). Isolation of a conditionally lethal temperature-sensitive pol III mutant showed that this enzyme is required for replicating the E. coli chromosome. In contrast, pol II remained an enigma until last year, when it was shown to be pivotal in restarting replication in UV-irradiated cells. Last year also saw the identification of a new class of DNA polymerases — the UmuC/DinB/Rev1p/Rad30 superfamily (TABLE 1) — on the basis of five conserved sequence motifs present in all of these proteins (FIG. 1). The yeast Rev1 protein had been shown to contain DNAtemplate-dependent DCMP TRANSFERASE activity nearly three years earlier, but it was not until 1999 that the other family members were isolated and shown to be capable of replicating DNA using all four bases. Biological functions have been established for some members, including the E. coli UmuD′ 2 C complex (now known as pol V), the yeast Rev1 protein and human DNA polymerase eta (pol η/Rad30). However, the functions of the remaining members of the UmuC/DinB/Rev1p/Rad30 polymerase superfamily are less certain. A feature common to many of these polymerases is their tendency to copy undamaged DNA with remarkably poor fidelity, whether or not they are involved in translesion synthesis. As its name suggests, translesion synthesis is the unimpaired copying of aberrant bases (see below) at which other cellular polymerases stall. With undamaged DNA, these low-fidelity polymerases incorporate an incorrect nucleotide once every 100–1,000 bases on average (TABLE 1). For comparison, normal polymerases that do not PROOFREAD misincorporate nucleotides in the range of once every 10–10 bases. Examples of low-fidelity polymerases include E. coli pol V, which preferentially misincorporates G opposite a 3′ T of a T–T 6–4 PHOTOPRODUCT; E. coli DNA polymerase IV (pol IV/DinB), which adds a nucleotide onto the end of a misaligned primer; Rev1p, which incorporates C opposite a non-coding ABASIC LESION; and human DNA polymerase iota (pol ι/Rad30B), which favours misincorporation of G opposite T on undamaged DNA. All of these events lead to mutation. There is also the remarkable case of pol η, which copies pyrimidine T–T DIMERS accurately, resulting in mutation avoidance at this type of DNA damage (FIG. 2). The number of DNA polymerases has now grown from 3 to 5 in E. coli, and from 5 to at least 14 and countTHE EXPANDING POLYMERASE UNIVERSE
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