title: Suppression of the DHX9 helicase induces premature senescence in human diploid fibroblasts in a p53-dependent manner.
abstract: DHX9 is an ATP-dependent DEXH box helicase with a multitude of cellular functions. Its ability to unwind both DNA and RNA, as well as aberrant, noncanonical polynucleotide structures, has implicated it in transcriptional and translational regulation, DNA replication and repair, and maintenance of genome stability. We report that loss of DHX9 in primary human fibroblasts results in premature senescence, a state of irreversible growth arrest. This is accompanied by morphological defects, elevation of senescence-associated β-galactosidase levels, and changes in gene expression closely resembling those encountered during replicative (telomere-dependent) senescence. Activation of the p53 signaling pathway was found to be essential to this process. ChIP analysis and investigation of nascent DNA levels revealed that DHX9 is associated with origins of replication and that its suppression leads to a reduction of DNA replication. Our results demonstrate an essential role of DHX9 in DNA replication and normal cell cycle progression.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Domenic
authors.initials: D
authors.lastname: Di Paola
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Abba
authors.initials: A
authors.lastname: Malina
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mills
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Kreps
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena D-07745, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Grosse
authors.affiliation: Department of Biological Science, Florida State University, Tallahassee, Florida 32306.
authors.forename: Hengli
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada,; Department of Oncology, McGill University, Montreal, Quebec H3A 1A3, Canada; The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3A 1A3, Canada, and.
authors.forename: Maria
authors.initials: M
authors.lastname: Zannis-Hadjopoulos
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm 171 77, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada,; Department of Oncology, McGill University, Montreal, Quebec H3A 1A3, Canada; The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3A 1A3, Canada, and. Electronic address: jerry.pelletier@mcgill.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology*; D016922:Cellular Senescence / Q000502:physiology*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000502:physiology*; D004171:Diploidy; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases
keywords: Cell Cycle; Cell Growth; DNA Replication; Helicase; Senescence; p53