Bitte benutzen Sie diese Referenz, um auf diese Ressource zu verweisen: doi:10.22028/D291-32861
Titel: Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence
VerfasserIn: Isermann, Anna
Mann, Carl
Rübe, Claudia E.
Sprache: Englisch
Titel: International Journal of Molecular Sciences
Bandnummer: 21
Heft: 23
Verlag/Plattform: MDPI
Erscheinungsjahr: 2020
Freie Schlagwörter: histone variant H2A.J
radiation-induced senescence
senescence-associated heterochromatin foci (SAHF)
DNA-SCARS
transmission electron microscopy (TEM)
senescence-associated secretory phenotype (SASP)
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: 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.
DOI der Erstveröffentlichung: 10.3390/ijms21239130
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-328610
hdl:20.500.11880/30458
http://dx.doi.org/10.22028/D291-32861
ISSN: 1422-0067
Datum des Eintrags: 27-Jan-2021
Bezeichnung des in Beziehung stehenden Objekts: Supplementary Materials
In Beziehung stehendes Objekt: http://www.mdpi.com/1422-0067/21/23/9130/s1
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Radiologie
Professur: M - Keiner Professur zugeordnet
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

Dateien zu diesem Datensatz:
Datei Beschreibung GrößeFormat 
ijms-21-09130.pdf6,94 MBAdobe PDFÖffnen/Anzeigen


Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons Creative Commons