Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence
| Autor: | Carl Mann, Anna Isermann, Claudia E. Rübe |
|---|---|
| Přispěvatelé: | Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Sénescence et stabilité génomique (SEN), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE12-0008,H2AJFUN,Analyse Fonctionnelle d'un Nouveau Variant d'Histone, H2A.J, en Sénescence(2017) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Senescence
DNA damage Heterochromatin [SDV]Life Sciences [q-bio] Catalysis Article Epigenesis Genetic Inorganic Chemistry Histones lcsh:Chemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Radiation Ionizing transmission electron microscopy (TEM) histone variant H2A.J Humans Physical and Theoretical Chemistry Molecular Biology lcsh:QH301-705.5 Spectroscopy DNA-SCARS Cellular Senescence 030304 developmental biology 0303 health sciences biology Organic Chemistry fungi senescence-associated heterochromatin foci (SAHF) Genetic Variation senescence-associated secretory phenotype (SASP) radiation-induced senescence General Medicine Phenotype Computer Science Applications Chromatin Cell biology Histone chemistry lcsh:Biology (General) lcsh:QD1-999 030220 oncology & carcinogenesis biology.protein DNA DNA Damage |
| Zdroj: | International Journal of Molecular Sciences, Vol 21, Iss 9130, p 9130 (2020) International Journal of Molecular Sciences International Journal of Molecular Sciences, MDPI, 2020, 21 (23), ⟨10.3390/ijms21239130⟩ Volume 21 Issue 23 International Journal of Molecular Sciences, 2020, 21 (23), ⟨10.3390/ijms21239130⟩ |
| ISSN: | 1661-6596 1422-0067 |
| DOI: | 10.3390/ijms21239130⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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