HSP90 regulates DNA repair via the interaction between XRCC1 and DNA polymerase β

Qingming Fang, Burcu Inanc, Sandy Schamus, Xiao-hong Wang, Leizhen Wei, Ashley R. Brown, David Svilar, Kelsey F. Sugrue, Eva M. Goellner, Xuemei Zeng, Nathan A. Yates, Li Lan, Conchita Vens and Robert W. Sobol ()
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Qingming Fang: University of Pittsburgh School of Medicine
Burcu Inanc: The Netherlands Cancer Institute
Sandy Schamus: Hillman Cancer Center, University of Pittsburgh Cancer Institute
Xiao-hong Wang: Hillman Cancer Center, University of Pittsburgh Cancer Institute
Leizhen Wei: Hillman Cancer Center, University of Pittsburgh Cancer Institute
Ashley R. Brown: Hillman Cancer Center, University of Pittsburgh Cancer Institute
David Svilar: University of Pittsburgh School of Medicine
Kelsey F. Sugrue: Hillman Cancer Center, University of Pittsburgh Cancer Institute
Eva M. Goellner: University of Pittsburgh School of Medicine
Xuemei Zeng: Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences
Nathan A. Yates: Hillman Cancer Center, University of Pittsburgh Cancer Institute
Li Lan: Hillman Cancer Center, University of Pittsburgh Cancer Institute
Conchita Vens: The Netherlands Cancer Institute
Robert W. Sobol: University of Pittsburgh School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6513

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