Abstract
Cellular DNA repair processes are crucial to maintain genome stability and integrity. In DNA base excision repair, a tight heterodimer complex formed by DNA polymerase β (Polβ) and XRCC1 is thought to facilitate repair by recruiting Polβ to DNA damage sites. Here we show that disruption of the complex does not impact DNA damage response or DNA repair. Instead, the heterodimer formation is required to prevent ubiquitylation and degradation of Polβ. In contrast, the stability of the XRCC1 monomer is protected from CHIP-mediated ubiquitylation by interaction with the binding partner HSP90. In response to cellular proliferation and DNA damage, proteasome and HSP90-mediated regulation of Polβ and XRCC1 alters the DNA repair complex architecture. We propose that protein stability, mediated by DNA repair protein complex formation, functions as a regulatory mechanism for DNA repair pathway choice in the context of cell cycle progression and genome surveillance.
| Original language | English |
|---|---|
| Article number | 5513 |
| Journal | Nature Communications |
| Volume | 5 |
| DOIs | |
| State | Published - 2014 |
Bibliographical note
Funding Information:We thank Dr Hein te Riele (NKI) and Drs Jianfeng Li and Elise Fouquerrel (University of Pittsburgh) for valuable comments during the preparation of this manuscript; Andrea Braganza, Brittany Charsar, Tyler Seyco, Brianna Edwards, Charlie Fencil, Alyssa Stan-dlick, Nicholas Burton and Leah Mitchell for technical help. Recombinant human Polb was a generous gift from Dr S.H. Wilson (NIEHS). We also thank Dr Jing Hu (University of Pittsburgh) for providing the pcDNA-HA-Ubiquitin vector. This work was supported by grants from the National Institute of Health (NIH) (CA148629, GM087798, ES019498, ES021116, ES022291, GM099213, UL1-RR024153 and Ul1TR000005) to R.W.S. and by a grant from the Dutch Cancer Society to C.V. (NKI-2010-4877). This publication was also made possible by Pilot funds awarded to R.W.S. from the UPCI Cancer Center Support Grant from the National Institutes of Health (CA047904). Support for the UPCI Lentiviral Facility and the UPCI Flow Cytometry Facility was provided by the Cancer Center Support Grant from the National Institutes of Health (CA047904). This publication was also made possible by Grant Number UL1 TR0000005 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research to R.W.S. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCATS or NIH.
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)