title: HSP90 regulates DNA repair via the interaction between XRCC1 and DNA polymerase β.
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.
authors.affiliation: 1] Department of Pharmacology &Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA [2] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Fang
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam 1006BE, The Netherlands.
authors.forename: Burcu
authors.initials: B
authors.lastname: Inanc
authors.affiliation: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Schamus
authors.affiliation: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Xiao-hong
authors.initials: XH
authors.lastname: Wang
authors.affiliation: 1] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA [2] Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Leizhen
authors.initials: L
authors.lastname: Wei
authors.affiliation: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Brown
authors.affiliation: 1] Department of Pharmacology &Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA [2] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: David
authors.initials: D
authors.lastname: Svilar
authors.affiliation: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Kelsey F
authors.initials: KF
authors.lastname: Sugrue
authors.affiliation: 1] Department of Pharmacology &Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA [2] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goellner
authors.affiliation: Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zeng
authors.affiliation: 1] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA [2] Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, Pennsylvania 15213, USA [3] Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Yates
authors.affiliation: 1] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA [2] Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lan
authors.affiliation: 1] The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam 1006BE, The Netherlands [2] The Netherlands Cancer Institute, Division of Radiotherapy, Amsterdam 1006BE, The Netherlands.
authors.forename: Conchita
authors.initials: C
authors.lastname: Vens
authors.affiliation: 1] Department of Pharmacology &Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA [2] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA [3] Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D019951:DNA Polymerase beta