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DNA polymerase s (Pols) is recognized as an essential DNA repair protein [1], [2]. Although the smallest of the human DNA polymerases [3], [4], this 335–amino-acid protein is the primary DNA polymerase in the base excision repair (BER) pathway [5]. A majority of the 20,000 DNA lesions per day that each human cell is faced with are repaired by the BER pathway [6]. These include products of base depurination and depyrimidination (abasic sites), deamination of cytosine and 5-methylcytosine, oxidation products such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), thymine glycol and lipid peroxidation products, as well as methylation modifications such as N7-guanine [7], [8]. Failure to repair these spontaneous or endogenously induced DNA base lesions as well as the numerous base modifications that arise from environmental or exogenous sources can result in multiple cellular effects, including cell death, gene mutations, gene rearrangements, and/or decreased cell growth rate. Pols facilitates the repair of these base lesions in concert with different proteins of the BER pathway depending on the lesion [2], [7]. Once the base lesion is removed by one of 11 DNA glycosylase enzymes and the resulting abasic site is hydrolysed by the endonuclease APE1, Pols is recruited to the lesion via an interaction with the BER scaffold protein XRCC1 [9], [10] and the DNA damage sensor PARP1 [11]–[13]. Pols then conducts two essential enzymatic functions: 5′dRP lyase–mediated gap tailoring and DNA polymerase–mediated DNA synthesis to fill the gap [2], [3]. The 5′dRP lyase activity functions to “tailor” the gap by removing the sugar-phosphate residue that remains after APE1 cleaves the DNA backbone, and then the polymerase activity adds the newly synthesized nucleotide that was removed during repair. Considering the critical and essential role of these two enzymatic activities, the important protein–protein interactions between Pols and several BER proteins [14], as well as the increasing number of post-translational modifications suggested to affect Pols function and stability [15], it may not be surprising that a significant number of somatic mutations in POLB have been observed in cancer (Table 1). Within the 33 Kb POLB gene (PubMed geneID #5423), as many as 567 SNPs have been identified (see dbSNP). However, only 34 SNPs are in or near the coding region (22 are found in exons), and only two have been confirmed in larger cohorts. These two germline POLB mutants (R137Q; rs12678588 and P242R; rs3136797) have been reported to be present in as much as 0.6% and 2.4% of the human population, respectively [16], [17]. However, little is known about the functional impact that results from these single amino acid alterations. An earlier study on the Pols (R137Q) mutant (rs12678588) suggested that the R137Q mutation impairs function of the purified protein. Further, when produced in mouse cells, the R137Q mutant protein interfered with Pols binding to PCNA [18] and the response of mouse cells to DNA-damaging agents, although no information was provided on the impact of this mutation on genome stability. Whereas the Pols (P242R) mutant allele (rs3136797) has been linked with altered incidence of cancer in several studies [19]–[21], there have been few or no studies defining the impact of this SNP on Pols function, DNA repair capacity, and genome maintenance in human cells.

Genome Instability Caused by a Germline Mutation in the Human DNA Repair Gene POLB