A novel role of XRCC1 in the functions of a DNA polymerase β variant

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