title: ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage.
abstract: The nucleolus plays a major role in ribosome biogenesis. Most genotoxic agents disrupt nucleolar structure and function, which results in the stabilization/activation of p53, inducing cell cycle arrest or apoptosis. Likewise, transcription factor E2F1 as a DNA damage responsive protein also plays roles in cell cycle arrest, DNA repair, or apoptosis in response to DNA damage through transcriptional response and protein-protein interaction. Furthermore, E2F1 is known to be involved in regulating rRNA transcription. However, how E2F1 displays in coordinating DNA damage and nucleolar stress is unclear. In this study, we demonstrate that ATM-dependent E2F1 accumulation in the nucleolus is a characteristic feature of nucleolar stress in early response to DNA damage. We found that at the early stage of DNA damage, E2F1 accumulation in the nucleolus was an ATM-dependent and a common event in p53-suficient and -deficient cells. Increased nucleolar E2F1 was sequestered by the nucleolar protein p14ARF, which repressed E2F1-dependent rRNA transcription initiation, and was coupled with S phase. Our data indicate that early accumulation of E2F1 in the nucleolus is an indicator for nucleolar stress and a component of ATM pathway, which presumably buffers elevation of E2F1 in the nucleoplasm and coordinates the diversifying mechanisms of E2F1 acts in cell cycle progression and apoptosis in early response to DNA damage.
authors.affiliation: Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing, PR China.
authors.forename: Ya-Qiong
authors.initials: YQ
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing, PR China.
authors.forename: Guo-Shun
authors.initials: GS
authors.lastname: An
authors.affiliation: Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing, PR China.
authors.forename: Ju-Hua
authors.initials: JH
authors.lastname: Ni
authors.affiliation: Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing, PR China.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing, PR China; Department of Biochemistry and Molecular Biology; Capital Medical University; Beijing, PR China.
authors.forename: Hong-Ti
authors.initials: HT
authors.lastname: Jia
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism*; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D020459:Genes, rRNA; D006801:Humans; D051379:Mice; D012270:Ribosomes / Q000378:metabolism*; D016196:S Phase; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D025803:Tumor Suppressor Protein p14ARF; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA damage; E2F1; nucleolar stress; p14ARF; rRNA promoter