Stability and sub-cellular localization of DNA polymerase ß is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress.
Nucleic Acids Res
; 47(12): 6269-6286, 2019 07 09.
Article
em En
| MEDLINE
| ID: mdl-31287140
ABSTRACT
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 ß (Polß), we find that mutation of this surface threonine residue impacts critical Polß protein-protein interactions. We show that proteasome-mediated degradation of Polß is regulated by both ubiquitin-dependent and ubiquitin-independent processes via unique protein-protein interactions. The ubiquitin-independent proteasome pathway regulates the stability of Polß in the cytosol via interaction between Polß and NAD(P)H quinone dehydrogenase 1 (NQO1) in an NADH-dependent manner. Conversely, the interaction of Polß with the scaffold protein X-ray repair cross complementing 1 (XRCC1) plays a role in the localization of Polß to the nuclear compartment and regulates the stability of Polß via a ubiquitin-dependent pathway. Further, we find that oxidative stress promotes the dissociation of the Polß/NQO1 complex, enhancing the interaction of Polß with XRCC1. Our results reveal that somatic mutations such as T304I in Polß impact critical protein-protein interactions, altering the stability and sub-cellular localization of Polß and providing mechanistic insight into how key protein-protein interactions regulate cellular responses to stress.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
NAD(P)H Desidrogenase (Quinona)
/
Estresse Oxidativo
/
DNA Polimerase beta
/
Proteína 1 Complementadora Cruzada de Reparo de Raio-X
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article