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To this end, we knocked down \u03b14 protein expression (\u03b14 KD) using siRNA in cultured H9c2 cardiomyocytes and confirmed the lack of DNA damage\/cell death by TUNEL staining and MTT assay. However, \u03b14 KD did increase the phosphorylation of p53 and ATM\/ATR substrates, decreased the expression of poly ADP-ribose polymerase and associated fragments. Expression of anti-apoptotic proteins Bcl-2 and Bcl-xL was reduced, whereas expression of pro-apoptotic BAX protein did not change. Alpha4 KD reduced basal H2AX Ser139 phosphorylation, whereas adenoviral-mediated re-expression of \u03b14 protein following \u03b14 KD, restored basal H2AX phosphorylation at Ser139. The sensitivity of H9c2 cardiomyocytes to doxorubicin-induced DNA damage and cytotoxicity was augmented by \u03b14 KD. Adenoviral-mediated overexpression of \u03b14 protein in ARVM increased PP2AC expression and augmented H2AX Ser139 phosphorylation in response to doxorubicin. Furthermore, pressure overload-induced heart failure was associated with reduced \u03b14 protein expression, increased ATM\/ATR protein kinase activity, increased H2AX expression and Ser139 phosphorylation. Hence, this study describes the significance of altered \u03b14 protein expression in the regulation of DNA damage, cardiomyocyte cell death and heart failure.<\/jats:p>","DOI":"10.1038\/s41598-021-85616-5","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T16:47:41Z","timestamp":1616086061000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Regulation of cardiomyocyte DNA damage and cell death by the type 2A protein phosphatase regulatory protein alpha4"],"prefix":"10.1038","volume":"11","author":[{"given":"Jonathan","family":"Cowan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Longman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0061-1111","authenticated-orcid":false,"given":"Andrew K.","family":"Snabaitis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"85616_CR1","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.4049\/jimmunol.154.6.2714","volume":"154","author":"S Inui","year":"1995","unstructured":"Inui, S. et al. 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