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The expanding polymerase universe

Abstract

Over the past year, the number of known prokaryotic and eukaryotic DNA polymerases has exploded. Many of these newly discovered enzymes copy aberrant bases in the DNA template over which 'respectable' polymerases fear to tread. The next step is to unravel their functions, which are thought to range from error-prone copying of DNA lesions, somatic hypermutation and avoidance of skin cancer, to restarting stalled replication forks and repairing double-stranded DNA breaks.

Key Points

  • Over the past year, the number of known prokaryotic and eukaryotic DNA polymerases has exploded. These newly discovered polymerases, which form the UmuC/DinB/Rev1p/Rad30 superfamily, copy aberrant bases in the DNA template.

  • The 'SOS' regulon in Escherichia coli is thought to be induced in response to regions of single-stranded DNA (a hallmark of damaged DNA). Two SOS genes, umuC and umuD, are required for replication past lesions in the DNA template.

    ? UmuC and UmuD′ (the active form of UmuD) interact to form a tight complex, UmuD′2C (polymerase V), with intrinsic DNA polymerase activity.

  • Polymerase V (pol V) cannot copy damaged DNA by itself. A multiprotein system (known as the pol V mutasome) consisting of pol V, RecA, single-stranded binding protein and β/γ complex (where β is the processivity clamp and γ the clamp-loader component of the replicative polymerase III holoenzyme) is required.

  • E. coli polymerase IV (DinB) is believed to copy undamaged DNA at stalled replication forks, which arise in vivo from mismatched or misaligned primer ends that are not proofread.

  • Saccharomyces cerevisiae Rev1p seems to have two distinct functions in copying DNA damage. It can act as a template-dependent dCMP transferase and can also facilitate translesion synthesis by another polymerase, most probably polymerase ζ (the Rev3 and Rev7 proteins).

  • DNA polymerase η, a human homologue of the yeast Rad30 protein, was identified as the product of the XPV gene last year. People who carry defects in XP genes show increased susceptibility to sunlight-induced skin cancer.

  • Somatic hypermutation, which is one of the processes responsible for generating antibody variants in humans, may involve error-prone DNA polymerases.

  • Errant polymerases have to show up where and when they are needed. One possibility is that they might always be present at the replication fork, perhaps bound to the replication complex.

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Figure 1: Representative members of the UmuC/DinB/Rev1p/Rad30 superfamily.
Figure 2: Biochemical properties of new polymerases.
Figure 3: The pol V mutasome.
Figure 4: Rev1p/pol ζ lesion bypass.
Figure 5: Genetic elements required for somatic hypermutation in the kappa light-chain immunoglobulin gene.
Figure 6: Models for somatic hypermutation by an error-prone polymerase.

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Acknowledgements

This work was supported by grants from the National Institutes of Health. I want to express heartfelt gratitude to my collaborators, Roger Woodgate, Mike O'Donnell, John-Stephen Taylor, Kevin McEntee and especially to Hatch Echols. I also want to express my sincere appreciation to the students in my laboratory, Phuong Pham, Mengjia Tang, Xuan Shen, Irina Bruck and Jeffrey Bertram.

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The DNA template-directed reaction catalysed by the yeast Rev1 protein, where C is favoured for incorporation opposite an abasic template site, and to a much lesser extent opposite a normal G site.

PROOFREADING

Excision of a misincorporated nucleotide at a growing 3′-primer end by a 3′ exonuclease associated with the polymerase.

T?T 6?4 PHOTOPRODUCT

A form of damage occurring when DNA is exposed to UV radiation, in which a covalent bond is formed between the 6 and 4 pyrimidine ring positions, coupling adjacent thymines on the same DNA strand.

ABASIC LESION

A common form of DNA damage in which a base is lost from a strand of DNA, spontaneously or by the action of DNA repair enzymes such as apurinic endonucleases or uracil glycosylase, while leaving the phosphodiester bond intact.

T?T DIMER

A form of damage occurring when DNA is exposed to UV radiation, in which two covalent bonds are formed between both the 5 and 6 positions of the pyrimidine ring on adjacent thymines located on the same DNA strand.

NUCLEOTIDE-EXCISION REPAIR

The main pathway for removal of UV-damaged bases.

REPLICATION FORK

Site in double-stranded DNA at which the template strands are separated, allowing a newly formed copy of the DNA to be synthesized, with the fork moving in the direction of leading strand synthesis.

DISTRIBUTIVE POLYMERASE

A polymerase that dissociates from the primer?template DNA after incorporating one (or at most a few) nucleotides.

PROCESSIVITY CLAMP

A doughnut-shaped protein complex that threads the DNA through its hole while tethering the polymerase to DNA, typically increasing the processivity of the polymerase (the number of nucleotides incorporated into DNA per polymerase?template binding event).

CLAMP LOADER

A protein complex that binds and then assembles the processivity clamp onto the DNA at a 3′-OH primer end, in a reaction requiring ATP.

GENETIC COMPLEMENTATION GROUPS

A distinct group of genes coding for separate polypeptides (proteins) required in the same biological pathway.

V(D)J RECOMBINATION

The site-specific recombination of immunoglobulin coding regions from multiple copies in the germ line to just one variable (V), one diversity (D) and one joining (J) region in the process of forming a functional immunoglobulin gene in B cells.

GERMINAL CENTRE

A highly organized structure that develops around follicles in peripheral lymphoid organs, such as the spleen and lymph nodes, in which B cells undergo rapid proliferation and selection on formation of antigen?antibody complexes during the immune response.

TRANSITION

A point mutation in which a purine base (A or G) is substituted for a different purine base, and a pyrimidine base (C or T) is substituted for a different pyrimidine base, for example, an A?T→G?C transition.

TRANSVERSION

A point mutation in which a purine base is substituted for a pyrimidine base and vice versa, for example, an A?T→C?G transversion.

TERMINAL TRANSFERASE

An enzyme found primarily in the thymus gland that incorporates nucleotides randomly onto the 3′ end of single-stranded DNA (a non-templated reaction), in contrast to a polymerase, which incorporates nucleotides onto a 3′-primer-end in a double-stranded, template-directed reaction.

PRIMOSOME

A complex of proteins whose role is to initiate DNA synthesis by the de novo synthesis of an oligonucleotide RNA primer on a DNA template strand; a primosome is typically used to initiate synthesis at a replication origin or to re-initiate synthesis downstream of a stalled replication fork.

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Goodman, M., Tippin, B. The expanding polymerase universe. Nat Rev Mol Cell Biol 1, 101–109 (2000). https://doi.org/10.1038/35040051

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