Abstract
DNA polymerase β (Polβ) is considered the main repair DNA polymerase involved in the base excision repair (BER) pathway, which plays an important part in the repair of damaged DNA bases usually resulting from alkylation or oxidation. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that protein–protein interactions of Polβ with enzymes from the BER pathway increase the efficiency of damaged base repair in DNA. However natural single-nucleotide polymorphisms can lead to a substitution of functionally significant amino acid residues and therefore affect the catalytic activity of the enzyme and the accuracy of Polβ action. Up-to-date databases contain information about more than 8000 SNPs in the gene of Polβ. This review summarizes data on the in silico prediction of the effects of Polβ SNPs on DNA repair efficacy; available data on cancers associated with SNPs of Polβ; and experimentally tested variants of Polβ. Analysis of the literature indicates that amino acid substitutions could be important for the maintenance of the native structure of Polβ and contacts with DNA; others affect the catalytic activity of the enzyme or play a part in the precise and correct attachment of the required nucleotide triphosphate. Moreover, the amino acid substitutions in Polβ can disturb interactions with enzymes involved in BER, while the enzymatic activity of the polymorphic variant may not differ significantly from that of the wild-type enzyme. Therefore, investigation regarding the effect of Polβ natural variants occurring in the human population on enzymatic activity and protein–protein interactions is an urgent scientific task.
Highlights
IntroductionAlkylation, deamination, apurinization/apyrimidinization, and DNA strand break formation are only some of the many processes that lead to DNA damage [1–5]
The interaction of PARP1, polymerase β (Polβ), and APE1 with nick-containing DNA was shown by photoaffinity labeling of base excision repair (BER) proteins in a cell extract [37], indicating the interaction of these proteins during repair synthesis catalyzed by Polβ
Polβ is considered the main repair DNA polymerase involved in the BER pathway, which plays an important part in the repair of damaged heterocyclic bases usually resulting from alkylation or oxidation [38–40]
Summary
Alkylation, deamination, apurinization/apyrimidinization, and DNA strand break formation are only some of the many processes that lead to DNA damage [1–5]. The main task of DNA glycosylases and AP endonucleases is to quickly and accurately find the location of a modified base or apurinic/apyrimidinic site among a huge number of intact bases and to initiate the repair process. In the long-patch pathway, Polβ performs synthesis through strand displacement, generating a short flap DNA 2–10 nt long This flap DNA structure is removed by endonuclease. Polβ interacts with enzymes from BER, such as one of the bifunctional DNA glycosylases (NEIL1) [24], human AP endonuclease APE1 [25], XRCC1 [26–28], and PCNA [29] and PARP1 proteins. The interaction of PARP1, Polβ, and APE1 with nick-containing DNA was shown by photoaffinity labeling of BER proteins in a cell extract [37], indicating the interaction of these proteins during repair synthesis catalyzed by Polβ
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