Raising the Dead: A Mechanism for Pol Beta E295K Inactivity

Postdoc Assoc Ther Radiology
15 York St, New Haven, CT 06510-3221

DNA Polymerase Beta (Pol β) is involved in base excision repair and several variants of Pol β have been identified in numerous cancers. One of these variants is E295K, which was identified in gastric and colon cancers. It has been previously characterized as a biologically inactive polymerase that is able to transform cells.  We have recently observed through crystallographic methods that E295K is able to bind dCTP.  Further biochemical analysis revealed E295K is able to incorporate dTTP opposite template A, as well as misincorporate dCTP opposite template A, at an extremely slow rate.  Although our findings show that this enzyme is still drastically impaired, our data suggest that E295K prefers to bind to dCTP over dTTP, but is unable to incorporate dCTP into the DNA.  /In /vivo, Pol β is likely to bind dCTP at lower concentrations, resulting in a ‘dead’ polymerase.  This can lead to an increase in double strand DNA breaks, chromosomal instability, and eventually cancer.   Overall, our data suggest a potential mechanism of pol β driven carcinogenesis.