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Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A\u2010T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA\u2010seq analysis of A\u2010T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A\u2010T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A\u2010T cells. We observed in them a robust activation of interferon\u2010stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non\u2010canonical cGAS\u2010STING\u2010mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A\u2010T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence\u2010associated secretory phenotype (SASP) factors known for their paracrine pro\u2010fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A\u2010T patients and its associated symptoms, which develop as the patients advance in age.<\/jats:p>","DOI":"10.1111\/acel.13869","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T06:31:20Z","timestamp":1685514680000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Accelerated replicative senescence of ataxia\u2010telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns"],"prefix":"10.1111","volume":"22","author":[{"given":"Majd","family":"Haj","sequence":"first","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel Aviv University School of Medicine  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Levon","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel Aviv University School of Medicine  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel Aviv University School of Medicine  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa","family":"Hourvitz","sequence":"additional","affiliation":[{"name":"The Alexander Silberman Institute of Life Sciences The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6858-9462","authenticated-orcid":false,"given":"Judith","family":"Campisi","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging  Novato California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehuda","family":"Tzfati","sequence":"additional","affiliation":[{"name":"The Alexander Silberman Institute of Life Sciences The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Elkon","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel Aviv University School of Medicine  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Ziv","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel Aviv University School of Medicine  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1538-6060","authenticated-orcid":false,"given":"Yosef","family":"Shiloh","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry Tel Aviv University School of Medicine  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13468"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101653"},{"key":"e_1_2_10_4_1","unstructured":"AndrewsS. 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