Causes and consequences of DNA double-stranded breaks in cardiovascular disease.

The genome, whose stability is essential for survival, is incessantly exposed to internal and external stressors, which introduce an estimated 10⁴ to 10⁵ lesions, such as oxidation, in the nuclear genome of each mammalian cell each day. A delicate homeostatic balance between the generation and repair of DNA lesions maintains genomic stability. To initiate transcription, DNA strands unwind to form a transcription bubble and provide a template for the RNA polymerase II (RNAPII) complex to synthesize nascent RNA. The process generates DNA supercoils and introduces torsional stress. To enable RNAPII processing, the supercoils are released by topoisomerases by introducing strand breaks, including double-stranded breaks (DSBs). Thus, DSBs are intrinsic genomic features of gene expression. The breaks are quickly repaired upon processing of the transcription. DNA lesions and damaged proteins involved in transcription could impede the integrity and efficiency of RNAPII processing. The impediment, which is referred to as transcription stress, not only could lead to the generation of aberrant RNA species but also the accumulation of DSBs. The latter is particularly the case when topoisomerase processing and/or the repair mechanisms are compromised. The DSBs activate the DNA damage response (DDR) pathways to repair the damaged DNA and/or impose cell cycle arrest and cell death. In addition, the release of DSBs into the cytosol activates the cytosolic DNA-sensing proteins (CDSPs), which along with the nuclear DDR pathways induce the expression of senescence-associated secretory phenotype (SASP), cell cycle arrest, senescence, cell death, inflammation, and aging. The primary stimulus in hereditary cardiomyopathies is a mutation(s) in genes encoding the protein constituents of cardiac myocytes; however, the phenotype is the consequence of intertwined complex interactions among numerous stressors and the causal mutation(s). Increased internal DNA stressors, such as oxidation, alkylation, and cross-linking, are expected to be common in pathological conditions, including in hereditary cardiomyopathies. In addition, dysregulation of gene expression also imposes transcriptional stress and collectively with other stressors provokes the generation of DSBs. In addition, the depletion of nicotinamide adenine dinucleotide (NAD), which occurs in pathological conditions, impairs the repair mechanism and further facilitates the accumulation of DSBs. Because DSBs activate the DDR pathways, they are expected to contribute to the pathogenesis of cardiomyopathies. Thus, interventions to reduce the generation of DSBs, enhance their repair, and block the deleterious DDR pathways would be expected to impart salubrious effects not only in pathological states, as in hereditary cardiomyopathies but also aging.