Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response
Quaresma, Alexandre Jose Christino
Nickerson, Jeffrey A.
Green, Karin M.
Shaffer, Scott A.
Imbalzano, Anthony N.
Martin-Buley, Lori A.
Lian, Jane B.
Stein, Janet L.
Van Wijnen, Andre J.
Stein, Gary S.
UMass Chan AffiliationsProteomics and Mass Spectrometry Facility
Department of Biochemistry and Molecular Pharmacology
Department of Cell and Developmental Biology
Document TypeJournal Article
DNA damage response
Cell and Developmental Biology
MetadataShow full item record
AbstractCancer 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 (gammaH2AX). UV irradiation increases the interaction of BAZ1B with gammaH2AX and decreases histone H3 lysine 9 acetylation levels, which mark accessible chromatin. RUNX2 depletion prevents the BAZ1B-gammaH2AX 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.
SourceJ Cell Sci. 2015 Feb 15;128(4):728-40. doi: 10.1242/jcs.160051. Link to article on publisher's site.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/26453
Related ResourcesLink to Article in PubMed