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Open AccessArticle

Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence

1
Department of Radiation Oncology, Saarland University Hospital, Kirrbergerstrasse Building 6.5, 66421 Homburg/Saar, Germany
2
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 9130; https://doi.org/10.3390/ijms21239130
Received: 4 November 2020 / Revised: 28 November 2020 / Accepted: 28 November 2020 / Published: 30 November 2020
(This article belongs to the Special Issue Molecular Bases of Senescence)
Irreparable double-strand breaks (DSBs) in response to ionizing radiation (IR) trigger prolonged DNA damage response (DDR) and induce premature senescence. Profound chromatin reorganization with formation of senescence-associated heterochromatin foci (SAHF) is an essential epigenetic mechanism for controlling the senescence-associated secretory phenotype (SASP). To decipher molecular mechanisms provoking continuous DDR leading to premature senescence, radiation-induced DSBs (53BP1-foci) and dynamics of histone variant H2A.J incorporation were analyzed together with chromatin re-modeling in human fibroblasts after IR exposure. High-resolution imaging by transmission electron microscopy revealed that persisting 53BP1-foci developed into DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), consistently located at the periphery of SAHFs. Quantitative immunogold-analysis by electron microscopy revealed that H2A.J, steadily co-localizing with 53BP1, is increasingly incorporated into DNA-SCARS during senescence progression. Strikingly, shRNA-mediated H2A.J depletion in fibroblasts modified senescence-associated chromatin re-structuring and abolished SASP, thereby shutting down the production of inflammatory mediators. These findings provide mechanistic insights into biological phenomena of SASP and suggest that H2A.J inhibition could ablate SASP, without affecting the senescence-associated growth arrest. View Full-Text
Keywords: histone variant H2A.J; radiation-induced senescence; senescence-associated heterochromatin foci (SAHF); DNA-SCARS; transmission electron microscopy (TEM); senescence-associated secretory phenotype (SASP) histone variant H2A.J; radiation-induced senescence; senescence-associated heterochromatin foci (SAHF); DNA-SCARS; transmission electron microscopy (TEM); senescence-associated secretory phenotype (SASP)
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MDPI and ACS Style

Isermann, A.; Mann, C.; Rübe, C.E. Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence. Int. J. Mol. Sci. 2020, 21, 9130. https://doi.org/10.3390/ijms21239130

AMA Style

Isermann A, Mann C, Rübe CE. Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence. International Journal of Molecular Sciences. 2020; 21(23):9130. https://doi.org/10.3390/ijms21239130

Chicago/Turabian Style

Isermann, Anna; Mann, Carl; Rübe, Claudia E. 2020. "Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence" Int. J. Mol. Sci. 21, no. 23: 9130. https://doi.org/10.3390/ijms21239130

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