Several small-scale studies suggest that at least thirty percent of the 149 tumors examined to date express variants of DMA polymerase beta (Pol IS) gene and none of these mutations are common polymorphisms. This suggests that there is a link between mutations in Pol IS and cancer. Preliminary data from our laboratory shows that expression of the cancer-derived I260M and K289M Pol IS mutants in mouse cells results in cellular transformation. We have also shown that DMA synthesis by the K289M colon cancer associated and I260M prostate cancer-associated Pol IS mutant enzymes results in the induction of mutations. These results demonstrate that Pol IS cancer-associated mutants have functional phenotypes. Because Pol IS is a key enzyme in the base excision repair pathway, our results suggest that abnormal base excision repair by Pol IS enzyme variants contributes to human cancers. These studies provide the impetus to determine whether mutations in the Pol IS gene make a significant contribution to human cancer. Because colon carcinoma is responsible for ten percent of all deaths due to cancer, we are focusing on this disease. The broad long-term objectives of the proposed research are to determine if Pol IS is mutated in a high frequency of human tumors, to identify the types of Pol IS mutations in human tumors, and to determine if the Pol IS mutations we identify have a functional phenotype. These studies will be performed by determining the DNA sequences of the Pol (S gene from 650 colon tumors and comparing them to normal controls, to obtain the percentage of tumors that harbor Pol IS variants. These variants will be characterized in genetic and biochemical assays to determine if they have phenotypes that are consistent with cancer etiology. ? ?
| Donigan, Katherine A; Sun, Ka-wai; Nemec, Antonia A et al. (2012) Human POLB gene is mutated in high percentage of colorectal tumors. J Biol Chem 287:23830-9 |
| Sweasy, Joann B; Lauper, Julia M; Eckert, Kristin A (2006) DNA polymerases and human diseases. Radiat Res 166:693-714 |
