title: E2F1-mediated DNA damage is implicated in 8-Cl-adenosine-induced chromosome missegregation and apoptosis in human lung cancer H1299 cells.
abstract: Although E2F1-mediated DNA double-stranded breaks (DSBs) and tetraploid have been extensively studied, the role of E2F1 in mitotic catastrophe is still unknown. We have previously shown that 8-chloro-adenosine (8-Cl-Ado) induces DNA DSBs and aberrant mitosis in human lung cancer cells, followed by delayed apoptosis. Here, we demonstrate that E2F1-mediated DNA damage is implicated in 8-Cl-Ado-induced chromosome missegregation and apoptosis in lung cancer H1299 cells. We showed that E2F1 was accumulated upon 8-Cl-Ado-induced DNA DSBs. Induction of E2F1 by 8-Cl-Ado caused DNA damage in cycling cells including M cells. In contrast, silencing of E2F1 expression decreased 8-Cl-Ado-induced DNA DSBs, particularly eliminated E2F1-mediated mitotic DNA damage. Over-expression of E2F1 and/or 8-Cl-Ado exposure resulted in aberrant mitotic spindles and chromosome segregation errors. Furthermore, over-expression of E2F1 expression enhanced 8-Cl-Ado-induced apoptosis. Together, our data indicate that E2F1-mediated DNA damage, in particular mitotic DNA damage, is an important fraction of 8-Cl-Ado-induced DNA damage, which is implicated in 8-Cl-Ado-induced mitotic catastrophe and delayed apoptosis. Induction of E2F1 by 8-Cl-Ado may contribute at least partly to the drug-inhibited proliferation of cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Capital Medical University, You An Men 8, Beijing, 100069, People's Republic of China.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Han
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ji-Xiang
authors.initials: JX
authors.lastname: Cao
authors.forename: Ya-Qiong
authors.initials: YQ
authors.lastname: Jin
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Li
authors.forename: Ju-Hua
authors.initials: JH
authors.lastname: Ni
authors.forename: Guo-Shun
authors.initials: GS
authors.lastname: An
authors.forename: Yu-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Hong-Ti
authors.initials: HT
authors.lastname: Jia
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D020090:Chromosome Segregation / Q000187:drug effects / Q000235:genetics*; D002875:Chromosomes / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D057891:Tetraploidy; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C468783:H2AX protein, human; D006657:Histones; D034741:RNA, Small Interfering; D025803:Tumor Suppressor Protein p14ARF; D015762:2-Chloroadenosine; C075440:8-chloroadenosine
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