title: Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response.
abstract: Cancer cells exhibit modifications in nuclear architecture and transcriptional control. Tumor growth and metastasis are supported by RUNX family transcriptional scaffolding proteins, which mediate the assembly of nuclear-matrix-associated gene-regulatory hubs. We used proteomic analysis to identify RUNX2-dependent protein-protein interactions associated with the nuclear matrix in bone, breast and prostate tumor cell types and found that RUNX2 interacts with three distinct proteins that respond to DNA damage - RUVBL2, INTS3 and BAZ1B. Subnuclear foci containing these proteins change in intensity or number following UV irradiation. Furthermore, RUNX2, INTS3 and BAZ1B form UV-responsive complexes with the serine-139-phosphorylated isoform of H2AX (γH2AX). UV irradiation increases the interaction of BAZ1B with γH2AX and decreases histone H3 lysine 9 acetylation levels, which mark accessible chromatin. RUNX2 depletion prevents the BAZ1B-γH2AX interaction and attenuates loss of H3K9 and H3K56 acetylation. Our data are consistent with a model in which RUNX2 forms functional complexes with BAZ1B, RUVBL2 and INTS3 to mount an integrated response to DNA damage. This proposed cytoprotective function for RUNX2 in cancer cells might clarify its expression in chemotherapy-resistant and/or metastatic tumors.
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Seungchan
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA Institute of Biomedicine, Department of Biochemistry and Developmental Biology, FI-00014 University of Helsinki, Finland.
authors.forename: Alexandre J C
authors.initials: AJ
authors.lastname: Quaresma
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nickerson
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Green
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Imbalzano
authors.affiliation: Department of Biochemistry & Vermont Cancer Center, University of Vermont Medical School, Burlington, VT 05405, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Martin-Buley
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA Department of Biochemistry & Vermont Cancer Center, University of Vermont Medical School, Burlington, VT 05405, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA Department of Biochemistry & Vermont Cancer Center, University of Vermont Medical School, Burlington, VT 05405, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA Departments of Orthopedic Surgery & Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street S.W., MSB 3-69, Rochester, MN 55905, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA Department of Biochemistry & Vermont Cancer Center, University of Vermont Medical School, Burlington, VT 05405, USA gary.stein@uvm.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000107:Acetylation; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000378:metabolism*; D014466:Ultraviolet Rays; D000092468:Bromodomain Containing Proteins
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D006657:Histones; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins; C468783:H2AX protein, human; C543505:INTS3 protein, human; C493709:RUNX2 protein, human; C122079:RUVBL2 protein, human
keywords: BAZ1B; Breast; Cancer; DNA damage response; INTS3; Nuclear matrix; Osteosarcoma; Prostate; Proteomics; RUNX2