Cellular roles of DNA polymerase beta

Abstract

Since its discovery and purification in 1971, DNA polymerase ß (Pol ß) is one of the most well-studied DNA polymerases. Pol ß is a key enzyme in the base excision repair (BER) pathway that functions in gap filling DNA synthesis subsequent to the excision of damaged DNA bases. A major focus of our studies is on the cellular roles of Pol ß. We have shown that germline and tumor-associated variants of Pol ß catalyze aberrant BER that leads to genomic instability and cellular transformation. Our studies suggest that Pol ß is critical for the maintenance of genomic stability and that it is a tumor suppressor. We have also shown that Pol ß functions during Prophase I of meiosis. Pol ß localizes to the synaptonemal complex and is critical for removal of the Spo11 complex from the 5' ends of double-strand breaks. Studies with Pol ß mutant mice are currently being undertaken to more clearly understand the function of Pol ß during meiosis. In this review, we will highlight our contributions from our studies of Pol ß germline and cancer-associated variants.

Keywords: DNA polymerase beta; fidelity of DNA synthesis; meiosis.

Figure 1

Mechanisms of genomic instability generated by Pol ß variant proteins. The DNA substrate for Pol ß is usually a single nucleotide gap with a 5’dRP group (red) that is generated upon excision of a damaged base. A mutator variant of Pol ß will remove the dRp group using its dRp lyase activity and fill in the gap in an error-prone manner, inducing mutations (denoted by X). A Pol ß variant with slow polymerase activity (low activity variant) will remove the dRp group, but not fill in all gaps in the cell, leading to the accumulation of BER intermediates and eventually to genomic instability. Failure to remove the dRp group by a Pol ß variant with slow dRp lyase activity will also result in the accumulation of BER intermediates and genomic instability.