title: Dynamics of histone H3.3 deposition in proliferating and senescent cells reveals a DAXX-dependent targeting to PML-NBs important for pericentromeric heterochromatin organization.
abstract: Oncogene-induced senescence is a permanent cell cycle arrest characterized by extensive chromatin reorganization. Here, we investigated the specific targeting and dynamics of histone H3 variants in human primary senescent cells. We show that newly synthesized epitope-tagged H3.3 is incorporated in senescent cells but does not accumulate in senescence-associated heterochromatin foci (SAHF). Instead, we observe that new H3.3 colocalizes with its specific histone chaperones within the promyelocytic leukemia nuclear bodies (PML-NBs) and is targeted to PML-NBs in a DAXX-dependent manner both in proliferating and senescent cells. We further show that overexpression of DAXX enhances targeting of H3.3 in large PML-NBs devoid of transcriptional activity and promotes the accumulation of HP1, independently of H3K9me3. Loss of H3.3 from pericentromeric heterochromatin upon DAXX or PML depletion suggests that the targeting of H3.3 to PML-NBs is implicated in pericentromeric heterochromatin organization. Together, our results underline the importance of the replication-independent chromatin assembly pathway for histone replacement in non-dividing senescent cells and establish PML-NBs as important regulatory sites for the incorporation of new H3.3 into chromatin.
authors.affiliation: Departement of Gynecology; University Hospital Zürich; Schlieren, Switzerland.
authors.forename: Armelle
authors.initials: A
authors.lastname: Corpet
authors.affiliation: Departement of Gynecology; University Hospital Zürich; Schlieren, Switzerland.
authors.forename: Teresa
authors.initials: T
authors.lastname: Olbrich
authors.affiliation: Departement of Gynecology; University Hospital Zürich; Schlieren, Switzerland.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gwerder
authors.affiliation: Departement of Gynecology; University Hospital Zürich; Schlieren, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fink
authors.affiliation: Departement of Gynecology; University Hospital Zürich; Schlieren, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Stucki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000378:metabolism; D004276:DNA, Satellite / Q000378:metabolism; D022041:Euchromatin / Q000235:genetics / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism* / Q000648:ultrastructure; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004276:DNA, Satellite; D022041:Euchromatin; D006570:Heterochromatin; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: DAXX; H3.3; PML-NBs; chromatin dynamics; senescence