2. Academic Validation
  3. Suppression of the DHX9 helicase induces premature senescence in human diploid fibroblasts in a p53-dependent manner

Suppression of the DHX9 helicase induces premature senescence in human diploid fibroblasts in a p53-dependent manner

  • J Biol Chem. 2014 Aug 15;289(33):22798-22814. doi: 10.1074/jbc.M114.568535.
Teresa Lee 1,  Domenic Di Paola 1,  Abba Malina 1,  John R Mills 1,  Amina Kreps 1,  Frank Grosse 2,  Hengli Tang 3,  Maria Zannis-Hadjopoulos 4,  Ola Larsson 5,  Jerry Pelletier 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
  • 2 Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena D-07745, Germany.
  • 3 Department of Biological Science, Florida State University, Tallahassee, Florida 32306.
  • 4 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.
  • 5 Department of Oncology-Pathology, Karolinska Institute, Stockholm 171 77, Sweden.
  • 6 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.
PMID: 24990949 DOI: 10.1074/jbc.M114.568535
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.

Keywords

Cell Cycle; Cell Growth; DNA Replication; Helicase; Senescence; p53.

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