Journal
NATURE CELL BIOLOGY
Volume 21, Issue 9, Pages 1152-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0380-8
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Funding
- National Key R&D Program of China [2018YFA0800501, 2018YFA0507603]
- National Natural Science Foundation of China [31671177, 81630008, 81790621, 31521062, 81370234]
- Beijing Municipal Science & Technology Commission [Z171100000417006]
- Beijing Natural Science Foundation [5182010]
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Ca2+/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its delta 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-delta 9, the most abundant CaMKII-delta splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-delta 9, but not the previously well-studied CaMKII-delta 2 and CaMKII-delta 3, 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-delta 9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.
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