title: Differential DNA damage signalling and apoptotic threshold correlate with mouse epiblast-specific hypersensitivity to radiation.
abstract: Between implantation and gastrulation, mouse pluripotent epiblast cells expand enormously in number and exhibit a remarkable hypersensitivity to DNA damage. Upon low-dose irradiation, they undergo mitotic arrest followed by p53-dependent apoptosis, whereas the other cell types simply arrest. This protective mechanism, active exclusively after E5.5 and lost during gastrulation, ensures the elimination of every mutated cell before its clonal expansion and is therefore expected to greatly increase fitness. We show that the insurgence of apoptosis relies on the epiblast-specific convergence of both increased DNA damage signalling and stronger pro-apoptotic balance. Although upstream Atm/Atr global activity and specific γH2AX phosphorylation are similar in all cell types of the embryo, 53BP1 recruitment at DNA breaks is immediately amplified only in epiblast cells after ionizing radiation. This correlates with rapid epiblast-specific activation of p53 and its transcriptional properties. Moreover, between E5.5 and E6.5 epiblast cells lower their apoptotic threshold by enhancing the expression of pro-apoptotic Bak and Bim and repressing the anti-apoptotic Bcl-xL. Thus, even after low-dose irradiation, the cytoplasmic priming of epiblast cells allows p53 to rapidly induce apoptosis via a partially transcription-independent mechanism.
authors.affiliation: IFOM (FIRC Institute of Molecular Oncology), IFOM-IEO-Campus, Via Adamello 16, 20139 Milan, Italy la.audrey@outlook.fr francesco.blasi@ifom.eu.
authors.forename: Audrey
authors.initials: A
authors.lastname: Laurent
authors.affiliation: IFOM (FIRC Institute of Molecular Oncology), IFOM-IEO-Campus, Via Adamello 16, 20139 Milan, Italy la.audrey@outlook.fr francesco.blasi@ifom.eu.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000528:radiation effects*; D005855:Germ Layers / Q000528:radiation effects*; D051379:Mice; D008938:Mitosis; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D014965:X-Rays
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C498302:Trp53bp1 protein, mouse; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: Apoptosis; Cytoplasmic apoptotic priming; DNA damage response; Epiblast; Trp53bp1