Some subunits of the SWI/SNF complex function as tumor suppressors. However, underlying mechanisms are still incompletely defined. Here, we show that Srg3, a mouse homolog of BAF155 that function as a core subunit of this complex, suppresses tumorigenesis in vivo. DNA damage signals promoted Srg3 degradation by inducing p53. Deficiency of Srg3 promoted G1 cell-cycle arrest, but antagonized apoptotic response to DNA damage by robustly inducing p53 and p21 proteins. Srg3 heterozygous mice were prone to sarcoma formation, which was further enhanced by haploinsufficiency of p53. These tumors highly expressed p53 and p21 but lacked Srg3 expression. Our results establish a novel function of Srg3 in tumor suppression and provide insights into genetic pathways dictating tumor suppression by the SWI/SNF complex.