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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 ?-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.

SUBMITTER: Lee T 

PROVIDER: S-EPMC4132785 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Lee Teresa T   Di Paola Domenic D   Malina Abba A   Mills John R JR   Kreps Amina A   Grosse Frank F   Tang Hengli H   Zannis-Hadjopoulos Maria M   Larsson Ola O   Pelletier Jerry J  

The Journal of biological chemistry 20140702 33


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  ...[more]

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