Title: Modulation of trinucleotide repeat instability by DNA polymerase β polymorphic variant R137Q.
Authors: Ren, Yaou; Lai, Yanhao; Laverde, Eduardo E; Lei, Ruipeng; Rein, Hayley L; Liu, Yuan
Published In PLoS One, (2017)
Abstract: Trinucleotide repeat (TNR) instability is associated with human neurodegenerative diseases and cancer. Recent studies have pointed out that DNA base excision repair (BER) mediated by DNA polymerase β (pol β) plays a crucial role in governing somatic TNR instability in a damage-location dependent manner. It has been shown that the activities and function of BER enzymes and cofactors can be modulated by their polymorphic variations. This could alter the function of BER in regulating TNR instability. However, the roles of BER polymorphism in modulating TNR instability remain to be elucidated. A previous study has shown that a pol β polymorphic variant, polβR137Q is associated with cancer due to its impaired polymerase activity and its deficiency in interacting with a BER cofactor, proliferating cell nuclear antigen (PCNA). In this study, we have studied the effect of the pol βR137Q variant on TNR instability. We showed that pol βR137Q exhibited weak DNA synthesis activity to cause TNR deletion during BER. We demonstrated that similar to wild-type pol β, the weak DNA synthesis activity of pol βR137Q allowed it to skip over a small loop formed on the template strand, thereby facilitating TNR deletion during BER. Our results further suggest that carriers with pol βR137Q polymorphic variant may not exhibit an elevated risk of developing human diseases that are associated with TNR instability.
PubMed ID: 28475635
MeSH Terms: DNA Damage; DNA Polymerase beta/genetics*; DNA Polymerase beta/metabolism; DNA Repair*; DNA Replication; Humans; Trinucleotide Repeats*