Research Papers:

SWI/SNF complexes are required for full activation of the DNA-damage response

Stephanie L. Smith-Roe _, Jun Nakamura, Darcy Holley, Paul D. Chastain, Gary B. Rosson, Dennis A. Simpson, John R. Ridpath, David G. Kaufman, William K. Kaufmann and Scott J. Bultman

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Oncotarget. 2015; 6:732-745. https://doi.org/10.18632/oncotarget.2715

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Stephanie L. Smith-Roe1,5, Jun Nakamura2, Darcy Holley1, Paul D. Chastain II3,4, Gary B. Rosson1, Dennis A. Simpson3, John R. Ridpath3, David G. Kaufman3, William K. Kaufmann3, Scott J. Bultman1

1Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

2Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC, USA

3Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA

4Department of Biomedical Sciences, William Carey University, Hattiesburg, MS, USA

5Current address: Division of the National Toxicology Program, NIEHS, Research Triangle Park, NC, USA

Correspondence to:

Scott J. Bultman, e-mail: Scott_Bultman@med.unc.edu

Keywords: BRG1, BRM, tumor suppression, DNA damage response, chemotherapeutics

Received: September 29, 2014     Accepted: November 09, 2014     Published: January 07, 2015


SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM (also known as SMARCA2) as alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling complexes are required for mammalian development and are mutated in ~20% of all human primary tumors. Yet our knowledge of their tumor-suppressor mechanism is limited. To investigate the role of SWI/SNF complexes in the DNA-damage response (DDR), we used shRNAs to deplete BRG1 and BRM and then exposed these cells to a panel of 6 genotoxic agents. Compared to controls, the shRNA knockdown cells were hypersensitive to certain genotoxic agents that cause double-strand breaks (DSBs) associated with stalled/collapsed replication forks but not to ionizing radiation-induced DSBs that arise independently of DNA replication. These findings were supported by our analysis of DDR kinases, which demonstrated a more prominent role for SWI/SNF in the activation of the ATR-Chk1 pathway than the ATM-Chk2 pathway. Surprisingly, γH2AX induction was attenuated in shRNA knockdown cells exposed to a topoisomerase II inhibitor (etoposide) but not to other genotoxic agents including IR. However, this finding is compatible with recent studies linking SWI/SNF with TOP2A and TOP2BP1. Depletion of BRG1 and BRM did not result in genomic instability in a tumor-derived cell line but did result in nucleoplasmic bridges in normal human fibroblasts. Taken together, these results suggest that SWI/SNF tumor-suppressor activity involves a role in the DDR to attenuate replicative stress and genomic instability. These results may also help to inform the selection of chemotherapeutics for tumors deficient for SWI/SNF function.

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