Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response
Seungchan Yang1, Alexandre J C Quaresma2, Jeffrey A Nickerson1
1Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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.
Insights
RUNX2 protein complexes respond to DNA damage in cancer cells, interacting with proteins like BAZ1B and forming complexes that protect cells. This may explain RUNX2
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Cancer cells display altered nuclear architecture and transcriptional control.
- RUNX family proteins scaffold transcriptional complexes, supporting tumor growth and metastasis.
- RUNX2 is implicated in nuclear-matrix-associated gene regulation.
Purpose of the Study:
- To identify RUNX2-dependent protein interactions at the nuclear matrix in bone, breast, and prostate cancer cells.
- To investigate the role of RUNX2 in DNA damage response pathways.
- To elucidate the function of RUNX2-protein complexes in cancer cytoprotection.
Main Methods:
- Proteomic analysis to identify protein-protein interactions.
- UV irradiation to induce DNA damage.
- Immunofluorescence to visualize subnuclear foci.
- Western blotting to detect protein modifications (e.g., γH2AX) and acetylation levels.
Main Results:
- RUNX2 interacts with DNA damage-responsive proteins RUVBL2, INTS3, and BAZ1B.
- Subnuclear foci of these proteins change upon UV irradiation.
- RUNX2, INTS3, and BAZ1B form UV-responsive complexes with γH2AX.
- UV irradiation enhances BAZ1B-γH2AX interaction and reduces histone acetylation.
- RUNX2 depletion disrupts BAZ1B-γH2AX interaction and preserves histone acetylation.
Conclusions:
- RUNX2 forms functional complexes with BAZ1B, RUVBL2, and INTS3 to mediate an integrated DNA damage response.
- This cytoprotective role of RUNX2 in cancer cells may explain its association with chemotherapy resistance and metastasis.
- RUNX2's involvement in DNA repair pathways offers potential therapeutic targets.
More Related Videos
Related Concept Videos
01:38Nucleotide Excision Repair
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:08Nucleotide Excision Repair
01:08Nucleotide Excision Repair
01:37Epigenetic Regulation
X-chromosome...
01:46Epigenetic Regulation
02:23Abnormal Proliferation