We report increased self-DNA in cardiac myocyte cytosol, activation of the DNA damage response pathway, and the beneficial effects of blocking the cytosolic component of the DNA damage response pathway in a mouse model of desmoplakin-cardiomyopathy, which pro-inflammatory and pro-fibrotic cardiomyopathy with excess myocardial cell death. The gene discussed is DSP; the disease is cardiomyopathy.