Marian A J
Center for Cardiovascular Genetic Studies, Institute of Molecular Medicine, The University of Texas Health Science Center, 6770 Bertner Street, Suite C900A, Houston, TX, 77030, USA.
Mol Cell Biochem. 2025 Apr;480(4):2043-2064. doi: 10.1007/s11010-024-05131-9. Epub 2024 Oct 15.
The genome, whose stability is essential for survival, is incessantly exposed to internal and external stressors, which introduce an estimated 10 to 10 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.
基因组的稳定性对生存至关重要，但其不断受到内部和外部应激源的影响，据估计，这些应激源每天在每个哺乳动物细胞的核基因组中引入10到10个损伤，如氧化损伤。DNA损伤的产生与修复之间微妙的稳态平衡维持着基因组的稳定性。为了启动转录，DNA链解开形成转录泡，并为RNA聚合酶II（RNAPII）复合物合成新生RNA提供模板。这个过程会产生DNA超螺旋并引入扭转应力。为了使RNAPII能够进行转录，拓扑异构酶通过引入链断裂（包括双链断裂，DSB）来释放超螺旋。因此，DSB是基因表达的内在基因组特征。转录过程完成后，这些断裂会迅速修复。参与转录的DNA损伤和受损蛋白质可能会阻碍RNAPII转录过程的完整性和效率。这种阻碍被称为转录应激，它不仅会导致异常RNA种类的产生，还会导致DSB的积累。当拓扑异构酶的作用和/或修复机制受损时，这种情况尤其明显。DSB会激活DNA损伤反应（DDR）途径来修复受损的DNA，和/或导致细胞周期停滞和细胞死亡。此外，DSB释放到细胞质中会激活细胞质DNA感应蛋白（CDSP），这些蛋白与核DDR途径一起诱导衰老相关分泌表型（SASP）的表达、细胞周期停滞、衰老、细胞死亡、炎症和衰老。遗传性心肌病的主要刺激因素是编码心肌细胞蛋白质成分的基因突变；然而，其表型是众多应激源与致病突变之间复杂相互作用的结果。预计在包括遗传性心肌病在内的病理状态下，内部DNA应激源（如氧化、烷基化和交联）的增加很常见。此外，基因表达失调也会造成转录应激，并与其他应激源共同引发DSB的产生。此外，在病理状态下发生的烟酰胺腺嘌呤二核苷酸（NAD）耗竭会损害修复机制，并进一步促进DSB的积累。由于DSB会激活DDR途径，预计它们会导致心肌病的发病机制。因此，减少DSB的产生、增强其修复并阻断有害的DDR途径的干预措施不仅有望对遗传性心肌病等病理状态产生有益影响，而且对衰老也有作用。
