Dna polymerases and their role in genomic stability

This issue of Environmental and Molecular Mutagenesis is devoted to DNA polymerases. Mutagenesis is an active cellular process, and numerous types of mutations and chromosomal rearrangements are the direct result of DNA polymerase errors. Since the report of enzymatic synthesis of DNA in 1958 by Kornberg and coworkers [Adler et al., 1958; Bessman et al., 1958a,b; Kornberg et al. 1958; Lehman et al. 1958a,b] to the identification of the first eukaryotic DNA polymerase [Loeb, 1969] and to the more recent discoveries of translesion polymerases (for an early review see [Hubscher et al., 2000]), these enzymes have fascinated researchers and have been the focus of many careers. The maintenance of genome integrity depends on accurate DNA synthesis by polymerases during DNA replication, DNA repair, and recombination. Human cells contain at least 15 distinct DNA polymerases, yet the precise roles of the various enzymes have not been fully elucidated. The articles of this special issue cover DNA polymerases from bacteria, yeast, mice, and humans and highlight the importance of DNA polymerases for both generating somatic diversity and maintaining genetic stability, as well as the disease consequences of aberrant DNA polymerase function and/or regulation. The first article in the issue is a review from members of the Sweasy laboratory of mouse models for DNA polymerases [Menezes and Sweasy, 2012]. This article presents an overview of DNA polymerase families and proposed cellular functions and extensively describes the phenotypes of both knockout and knockin models. The following two articles are review articles focused on DNA polymerase delta. The Loeb laboratory provides a comprehensive discussion of the roles of polymerase delta in replication, repair, and genome maintenance in yeast, mice, and human cells [Prindle and Loeb, 2012]. The Lee laboratory’s article focuses on the evidence for regulation of polymerase delta in response to DNA damage [Lee et al., 2012]. Interestingly, the p12 subunit of polymerase delta is degraded upon DNA damage induced by oxygen and environmental agents. On the degradation of p12, polymerase delta becomes a heterotrimeric enzyme that catalyzes DNA synthesis, especially lesion bypass, with higher accuracy than the four-subunit enzyme. A review article from the Pavlov laboratory comprehensively discusses the roles of nucleotide pool quality and DNA replication fork dynamics in mutagenesis [Waisertreiger et al., 2012]. Two articles in the issue are focused on DNA repair pathways. The polymerases involved in intrastrand crosslink repair are reviewed by members of the Canman laboratory [Sharma and Canman, 2012]. After crosslinks become unhooked, translesion synthesis by polymerase zeta and Rev1 is essential for bypass of the lesion and for subsequent repair of the double-strand breaks. Several DNA polymerases of the X family function in eukaryotic nonhomologous end-joining (NHEJ) repair. A review of NHEJ with a focus on polymerases involved, including polymerases lambda and mu, is presented by the Ramsden laboratory [Ramsden and Asagoshi, 2012]. Several original research articles in this special issue focus on Y family DNA lesion bypass polymerases. Kannouche and coworkers investigated the regulation of polymerase eta and report that both the ubiquitin binding domain and the PCNA interacting peptide box are required for the retention of this polymerase at stalled replication forks, rather that its recruitment [Despras et al., 2012]. Members of the Beuning laboratory report on their use of the computational programs of THEMATICS and POOL to study the contribution of specific E. coli Pol IV residues to lesion bypass. They find that these programs accurately predict the roles of active site residues of this protein [Walsh et al., 2012]. Finally, mechanisms of spontaneous mutagenesis were investigated in two original articles. Kunkel and coworkers examined spontaneous mutagenesis in yeast strains that are deficient in nucleotide excision repair [Stone et al., 2012]. Their results demonstrate that spontaneous multiple mutations arise from DNA lesions that are bypassed by DNA polymerase zeta and suggest that such multiple mutations have the ability to drive multistage carcinogenesis in humans in a more rapid manner than single base