Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress

Nucleic Acids Res. 2019 Jul 9;47(12):6269-6286. doi: 10.1093/nar/gkz293.


Protein-protein interactions regulate many essential enzymatic processes in the cell. Somatic mutations outside of an enzyme active site can therefore impact cellular function by disruption of critical protein-protein interactions. In our investigation of the cellular impact of the T304I cancer mutation of DNA Polymerase β (Polβ), we find that mutation of this surface threonine residue impacts critical Polβ protein-protein interactions. We show that proteasome-mediated degradation of Polβ is regulated by both ubiquitin-dependent and ubiquitin-independent processes via unique protein-protein interactions. The ubiquitin-independent proteasome pathway regulates the stability of Polβ in the cytosol via interaction between Polβ and NAD(P)H quinone dehydrogenase 1 (NQO1) in an NADH-dependent manner. Conversely, the interaction of Polβ with the scaffold protein X-ray repair cross complementing 1 (XRCC1) plays a role in the localization of Polβ to the nuclear compartment and regulates the stability of Polβ via a ubiquitin-dependent pathway. Further, we find that oxidative stress promotes the dissociation of the Polβ/NQO1 complex, enhancing the interaction of Polβ with XRCC1. Our results reveal that somatic mutations such as T304I in Polβ impact critical protein-protein interactions, altering the stability and sub-cellular localization of Polβ and providing mechanistic insight into how key protein-protein interactions regulate cellular responses to stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Chromatin / enzymology
  • Colonic Neoplasms / genetics
  • DNA Polymerase beta / chemistry
  • DNA Polymerase beta / genetics
  • DNA Polymerase beta / metabolism*
  • Enzyme Stability
  • Humans
  • Mutation
  • NAD / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / metabolism*
  • Oxidative Stress*
  • Proteasome Endopeptidase Complex / metabolism
  • Ubiquitination
  • X-ray Repair Cross Complementing Protein 1 / metabolism*


  • Chromatin
  • X-ray Repair Cross Complementing Protein 1
  • XRCC1 protein, human
  • NAD
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • DNA Polymerase beta
  • POLB protein, human
  • Proteasome Endopeptidase Complex