The deoxyribose phosphate lyase of DNA polymerase β suppresses a processive DNA synthesis to prevent trinucleotide repeat instability

Trinucleotide repeat (TNR) instability is associated with over 42 neurodegenerative diseases and cancer, for which the molecular mechanisms remain to be elucidated. We have shown that the DNA base excision repair (BER) pathway and its central component, DNA polymerase beta (pol beta), in particular, its polymerase activity plays an active role in regulating somatic TNR instability. Herein, we revealed a unique role of the pol beta dRP lyase in preventing somatic TNR instability. We found that deficiency of pol beta deoxyribose phosphate (dRP) lyase activity locked the pol beta dRP lyase domain to a dRP group, and this 'tethered' pol beta to its template forcing the polymerase to perform a processive DNA synthesis. This subsequently promoted DNA strand slippage allowing pol beta to skip over a template loop and causing TNR deletion. We showed that the effects were eliminated by complementation of the dRP lyase deficiency with wild-type pol beta protein. The results indicate that pol beta dRP lyase activity restrained the pol beta-dRP interaction to suppress a pol beta processive DNA synthesis, thereby preventing TNR deletion. This further implicates a potential of pol beta dRP lyase inhibition as a novel treatment of TNR-expansion diseases.