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Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):169-74. doi: 10.1073/pnas.0809834106. Epub 2008 Dec 31.

Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence.

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  • 1Whitehead Institute for Biomedical Research and Ludwig Center for Molecular Oncology, 9 Cambridge Center, Cambridge, MA 02142, USA.

Abstract

Reactive oxygen species (ROS) appear to play a role in limiting both cellular and organismic lifespan. However, because of their pleiotropic effects, it has been difficult to ascribe a specific role to ROS in initiating the process of cellular senescence. We have studied the effects of oxidative DNA damage on cell proliferation, believing that such damage is of central importance to triggering senescence. To do so, we devised a strategy to decouple levels of 8-oxoguanine, a major oxidative DNA lesion, from ROS levels. Suppression of MTH1 expression, which hydrolyzes 8-oxo-dGTP, was accompanied by increased total cellular 8-oxoguanine levels and caused early-passage primary and telomerase-immortalized human skin fibroblasts to rapidly undergo senescence, doing so without altering cellular ROS levels. This senescent phenotype recapitulated several salient features of replicative senescence, notably the presence of senescence-associated beta-galactosidase (SA beta-gal) activity, apparently irreparable genomic DNA breaks, and elevation of p21(Cip1), p53, and p16(INK4A) tumor suppressor protein levels. Culturing cells under low oxygen tension (3%) largely prevented the shMTH1-dependent senescent phenotype. These results indicate that the nucleotide pool is a critical target of intracellular ROS and that oxidized nucleotides, unless continuously eliminated, can rapidly induce cell senescence through signaling pathways very similar to those activated during replicative senescence.

PMID:
19118192
[PubMed - indexed for MEDLINE]
PMCID:
PMC2629241
Free PMC Article

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