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

摘要: // Stephanie L. Smith-Roe 1, 5 , Jun Nakamura 2 Darcy Holley 1 Paul D. Chastain II 3, 4 Gary B. Rosson Dennis A. Simpson 3 John R. Ridpath David G. Kaufman William K. Kaufmann Scott J. Bultman Department of Genetics and Lineberger Comprehensive Cancer Center, University North Carolina, Chapel Hill, NC, USA Environmental Sciences Engineering, Pathology Laboratory Medicine, Biomedical Sciences, Carey University, Hattiesburg, MS, Current address : Division the National Toxicology Program, NIEHS, Research Triangle Park, Correspondence to: Bultman, e-mail: Scott_Bultman@med.unc.edu Keywords: BRG1, BRM, tumor suppression, DNA damage response, chemotherapeutics Received: September 29, 2014      Accepted: November 09, Published: January 07, 2015 ABSTRACT SWI/SNF complexes utilize BRG1 (also known as SMARCA4) or BRM SMARCA2) alternative catalytic subunits with ATPase activity to remodel chromatin. These chromatin-remodeling are required for mammalian development mutated in ~20% all human primary tumors. Yet our knowledge their tumor-suppressor mechanism is limited. To investigate role DNA-damage response (DDR), we used shRNAs deplete then exposed these cells a panel 6 genotoxic agents. Compared controls, shRNA knockdown were hypersensitive certain agents that cause double-strand breaks (DSBs) associated stalled/collapsed replication forks but not ionizing radiation-induced DSBs arise independently replication. findings supported by analysis DDR kinases, which demonstrated more prominent activation ATR-Chk1 pathway than ATM-Chk2 pathway. Surprisingly, γH2AX induction was attenuated topoisomerase inhibitor (etoposide) other including IR. However, this finding compatible recent studies linking TOP2A TOP2BP1. Depletion did result genomic instability tumor-derived cell line nucleoplasmic bridges normal fibroblasts. Taken together, results suggest involves attenuate replicative stress instability. may also help inform selection tumors deficient function.