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Our previous RNA interference-based screen of chromatin factors found that lysine methyltransferases including SETD8 and NSD2 inhibited the senescence program in cultured fibroblasts. Here, we report that loss of the zinc finger and homeobox protein 3 (ZHX3), a ubiquitously expressed transcription repressor, induced senescence-associated gene expression and mitochondrial\u2013nucleolar activation. Chromatin immunoprecipitation\u2013sequencing analyses of growing cells revealed that ZHX3 was enriched at the transcription start sites of senescence-associated genes such as the cyclin-dependent kinase inhibitor (<jats:italic>ARF-p16<jats:sup>INK4a<\/jats:sup><\/jats:italic>) gene and ribosomal RNA (rRNA) coding genes. ZHX3 expression was consistently downregulated in cells with replicative or oncogene-induced senescence. Mass spectrometry-based proteomics identified 28 proteins that interacted with ZHX3, including ATP citrate lyase and RNA metabolism proteins. Loss of ZHX3 or ZHX3-interaction partners by knockdown similarly induced the expression of <jats:italic>p16<jats:sup>INK4a<\/jats:sup><\/jats:italic> and rRNA genes. <jats:italic>Zhx3<\/jats:italic>-knockout mice showed upregulation of <jats:italic>p16<jats:sup>INK4a<\/jats:sup><\/jats:italic> in the testes, thymus and skeletal muscle tissues, together with relatively short survival periods in males. These data suggested that ZHX3 plays an essential role in transcriptional control to prevent cellular senescence.<\/jats:p>","DOI":"10.1371\/journal.pone.0262488","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T18:41:17Z","timestamp":1643308877000},"page":"e0262488","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Loss of the transcription repressor ZHX3 induces senescence-associated gene expression and mitochondrial-nucleolar 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