细胞生物学
基因组不稳定性
DNA
DNA修复
心肌病
DNA损伤
生物
遗传学
医学
心力衰竭
内科学
作者
Mao Zhang,Hua Gao,Dairu Liu,Xiaoming Zhong,Xiaolu Shi,Peng Yu,Li Jin,Yun Liu,Yan Tang,Yang Song,Jinghao Liu,Xinli Hu,Chuan-Yun Li,Lei Song,Jun Qin,Fujian Wu,Feng Lan,Yan Zhang,Rui‐Ping Xiao
标识
DOI:10.1038/s41556-019-0380-8
摘要
Ca2+/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its δ isoform is predominant in the heart. Excessive CaMKII activation plays a pivotal role in the pathogenesis of severe heart conditions, including myocardial infarction, cardiomyopathy and heart failure. However, the identity of CaMKII splice variants and the mechanism(s) underlying CaMKII-mediated cardiac pathology remain elusive. Here, we show that CaMKII-δ9, the most abundant CaMKII-δ splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-δ9, but not the previously well-studied CaMKII-δ2 and CaMKII-δ3, targets the ubiquitin-conjugating enzyme E2T (UBE2T) for phosphorylation and degradation, disrupting UBE2T-dependent DNA repair and leading to the accumulation of DNA damage and genome instability. These findings not only reveal a crucial role of CaMKII in the regulation of DNA repair, but also mark the CaMKII-δ9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.
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