A Novel Role of XRCC1 in the Functions of a DNA Polymerase β Variant

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Abstract
In the base excision repair pathway, wild-type DNA polymerase β (WT polβ) provides most of the gap filling synthesis. A truncated polβ protein (polβΔ), expressed in primary colorectal and breast tumors and in a primary culture of renal cell carcinoma, inhibits the gap filling synthesis and DNA binding activities of WT polβ. However, a purified recombinant polβΔ does not inhibit a purified WT polβ. To determine the dominant inhibitory activity of polβΔ, we examined interactions of purified polβΔ with X-ray cross complementing group 1 (XRCC1), poly(ADP-ribose) polymerase (PARP), and apurinic endonuclease (Ape) proteins. All of these proteins interact with polβΔ in vitro and in vivo. The polβΔ protein can fill one nucleotide gap by inserting a base at the AP site, whereas a presumed binary complex of polβΔ and XRCC1 cannot. However, this binary complex not only suppresses gap filling synthesis activity of WT polβ but also binds more strongly to gapped DNA than WT polβ bound to XRCC1. These results are the first to suggest that XRCC1 is directly involved in the dominant negative activity of truncated polβ, possibly leading to the genomic instability characteristic of tumor cells.