title: Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer.
abstract: Survivin is an oncogene that functions in cancer cell cytoprotection and mitosis. Here we report that differential expression in cancer cells of a C-terminal splice variant of survivin, termed survivin-ΔEx3, is tightly associated with aggressive disease and markers of unfavorable prognosis. In contrast to other survivin variants, survivin-ΔEx3 localized exclusively to nuclei in tumor cells and was phosphorylated at multiple residues by the checkpoint kinase Chk2 during DNA damage. Mutagenesis of the Chk2 phosphorylation sites enhanced the stability of survivin-ΔEx3 in tumor cells, inhibited the expression of phosphorylated H2AX (γH2AX) in response to double-strand DNA breaks, and impaired growth after DNA damage. DNA damage induced Chk2 phosphorylation, stabilization of p53, induction of the cyclin-dependent kinase inhibitor p21, and homologous recombination-induced repair were not affected. In vivo, active Chk2 was detected at the earliest stages of the colorectal adenoma-to-carcinoma transition, persisted in advanced tumors, and correlated with increased survivin expression. Together, our findings suggest that Chk2-mediated phosphorylation of survivin-ΔEx3 contributes to a DNA damage-sensing checkpoint that may affect cancer cell sensitivity to genotoxic therapies.
authors.affiliation: Prostate Cancer Discovery and Development Program, Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.forename: Michele
authors.initials: M
authors.lastname: Tavecchio
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.forename: Jagadish C
authors.initials: JC
authors.lastname: Ghosh
authors.forename: Takehiko
authors.initials: T
authors.lastname: Dohi
authors.forename: Alice
authors.initials: A
authors.lastname: Faversani
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Tanigawa
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D017931:DNA Primers; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D016296:Mutagenesis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases