The Pathogenic Role of the DNA Double-Stranded Breaks in Hereditary Cardiomyopathies

Hereditary cardiomyopathies are caused primarily by mutations in genes encoding the protein constituents of cardiac myocytes. The mutation imparts biochemical, mechanical, and metabolic stresses, which not only induce the cardiomyopathy phenotype but also damage the nuclear and mitochondrial DNA, through oxidation, alkylation, cross-linking, and others. The DNA lesions, if unrepaired, cause replication and transcription stress, and activate the DNA damage response (DDR) pathways, which are composed of the repair, cell cycle checkpoint, and cytosolic DNA-sensing protein pathways. The DDR pathways provoke cell cycle arrest, instigate an interferon response, activate the nuclear factor Kappa B pathway. The induced gene expression causes inflammation, cell death, senescence, fibrosis, and organ dysfunction.