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Though multiple changes are known to be initiated by aberrant DUX4 expression, the downstream events initiated by DUX4 remain incompletely understood. In this study, we examined plausible downstream events initiated by DUX4. First, we found that nucleocytoplasmic protein export appeared to be decreased upon DUX4 expression as indicated by nuclear accumulation of a shuttle-GFP reporter. Second, building on studies from other labs, we showed that phospho(Ser139)-H2AX (\u03b3H2AX), an indicator of double-strand DNA breaks, accumulated both in human FSHD1 myotube nuclei upon endogenous DUX4 expression and in Bax-\/-;Bak-\/- (double knockout), SV40-immortalized mouse embryonic fibroblasts upon exogenous DUX4 expression. In contrast, DUX4-induced caspase 3\/7 activation was prevented in Bax-\/-;Bak-\/- double knockout SV40-MEFs, but not by single knockouts of Bax, Bak, or Bid. Thus, aberrant DUX4 expression appeared to alter nucleocytoplasmic protein transport and generate double-strand DNA breaks in FSHD1 myotube nuclei, and the Bax\/Bak pathway is required for DUX4-induced caspase activation but not \u03b3H2AX accumulation. These results add to our knowledge of downstream events induced by aberrant DUX4 expression and suggest possibilities for further mechanistic investigation.<\/jats:p>","DOI":"10.1242\/bio.059145","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T11:06:12Z","timestamp":1645527972000},"source":"Crossref","is-referenced-by-count":10,"title":["Downstream events initiated by expression of FSHD-associated DUX4: Studies of nucleocytoplasmic transport, \u03b3H2AX accumulation, and Bax\/Bak-dependence"],"prefix":"10.1242","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7607-1380","authenticated-orcid":false,"given":"Isabel F.","family":"Masteika","sequence":"first","affiliation":[{"name":"Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8858-7851","authenticated-orcid":false,"given":"Anvitha","family":"Sathya","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6563-8521","authenticated-orcid":false,"given":"Sachiko","family":"Homma","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-5436","authenticated-orcid":false,"given":"Bess M.","family":"Miller","sequence":"additional","affiliation":[{"name":"Biological & Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick M.","family":"Boyce","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5273-2201","authenticated-orcid":false,"given":"Jeffrey Boone","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"2022022211060568100_BIO059145C1","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1016\/j.yexcr.2008.12.007","article-title":"Explanation for excessive DNA single-strand breaks and endogenous repair foci in pluripotent mouse embryonic stem cells","volume":"315","author":"Ban\u00e1th","year":"2009","journal-title":"Exp. 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