Human DNA polymerase β polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the cellular base excision repair capacity |
| |
| Authors: | Zhigang Guo Li Zheng Huifang Dai Mian Zhou Hong Xu and Binghui Shen |
| |
| Affiliation: | Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA |
| |
| Abstract: | DNA polymerase β (Pol β) is a key enzyme in DNA base excision repair, and an important factor for maintaining genome integrity and stability. More than 30% of human tumors characterized to date express DNA Pol β variants, many of which result from a single nucleotide residue substitution. However, in most cases, their precise functional deficiency and relationship to cancer susceptibility are still unknown. In the current work, we show that a polymorphism encoding an arginine to glutamine substitution, R137Q, has lower polymerase activity. The substitution also affects the interaction between Pol β and proliferating cell nuclear antigen (PCNA). These defects impair the DNA repair capacity of Pol β in reconstitution assays, as well as in cellular extracts. Expression of wild-type Pol β in pol β−/− mouse embryonic fibroblast (MEF) cells restored cellular resistance to DNA damaging reagents such as methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU), while expression of R137Q in pol β−/− MEF cells failed to do so. These data indicate that polymorphisms in base excision repair genes may contribute to the onset and development of cancers. |
| |
| Keywords: | |
|
|
