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To investigate how abrupt changes in chromatin compaction alter these dynamics and affect DSB processing and repair, we exposed irradiated cells to hypotonic stress (HypoS). Densitometric and chromosome-length analyses show that HypoS transiently decompacts chromatin without inducing histone modifications known from regulated local chromatin decondensation, or changes in Micrococcal Nuclease (MNase) sensitivity. HypoS leaves undisturbed initial stages of DNA-damage-response (DDR), such as radiation-induced ATM activation and H2AX-phosphorylation. However, detection of ATM-pS1981, \u03b3-H2AX and 53BP1 foci is reduced in a protein, cell cycle phase and cell line dependent manner; likely secondary to chromatin decompaction that disrupts the focal organization of DDR proteins. While HypoS only exerts small effects on classical nonhomologous end-joining (c-NHEJ) and alternative end-joining (alt-EJ), it markedly suppresses homologous recombination (HR) without affecting DNA end-resection at DSBs, and clearly enhances single-strand annealing (SSA). These shifts in pathway engagement are accompanied by decreases in HR-dependent chromatid-break repair in the G2-phase, and by increases in alt-EJ and SSA-dependent chromosomal translocations. Consequently, HypoS sensitizes cells to ionizing radiation (IR)-induced killing. We conclude that HypoS-induced global chromatin decompaction compromises regulated chromatin dynamics and genomic stability by suppressing DSB-processing by HR, and allowing error-prone processing by alt-EJ and SSA.<\/jats:p>","DOI":"10.3390\/ijms222010957","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T21:45:32Z","timestamp":1633988732000},"page":"10957","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Disruption of Chromatin Dynamics by Hypotonic Stress Suppresses HR and Shifts DSB Processing to Error-Prone SSA"],"prefix":"10.3390","volume":"22","author":[{"given":"Lisa Marie","family":"Krieger","sequence":"first","affiliation":[{"name":"Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Mladenov","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-1006","authenticated-orcid":false,"given":"Aashish","family":"Soni","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilen","family":"Demond","sequence":"additional","affiliation":[{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Stuschke","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site University Hospital Essen, German Cancer Research Center (DKFZ), 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Iliakis","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/362709a0","article-title":"Instability and decay of the primary structure of DNA","volume":"362","author":"Lindahl","year":"1993","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/85798","article-title":"DNA double-strand breaks: Signaling, repair and the cancer connection","volume":"27","author":"Khanna","year":"2001","journal-title":"Nat. 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