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

Priyamvada Rai, Tamer T. Onder, Jennifer J. Young, Jose L. McFaline, Bo Pang, Peter C. Dedon, Robert A. Weinberg

Research output: Contribution to journalArticle

108 Citations (Scopus)

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 p16INK4A 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.

Original languageEnglish
Pages (from-to)169-174
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number1
DOIs
StatePublished - Jan 6 2009

Fingerprint

Cell Aging
Reactive Oxygen Species
Nucleotides
Cyclin-Dependent Kinase Inhibitor p16
Phenotype
DNA Breaks
Telomerase
beta-Galactosidase
DNA Damage
Fibroblasts
Cell Proliferation
Oxygen
Skin
DNA
Neoplasms
8-hydroxyguanine

Keywords

  • 8-oxoguanine
  • DNA damage
  • p53
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • General

Cite this

Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence. / Rai, Priyamvada; Onder, Tamer T.; Young, Jennifer J.; McFaline, Jose L.; Pang, Bo; Dedon, Peter C.; Weinberg, Robert A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 1, 06.01.2009, p. 169-174.

Research output: Contribution to journalArticle

Rai, Priyamvada ; Onder, Tamer T. ; Young, Jennifer J. ; McFaline, Jose L. ; Pang, Bo ; Dedon, Peter C. ; Weinberg, Robert A. / Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 1. pp. 169-174.
@article{c471e1b7a4bc4a0cbd905eb4f3c47e04,
title = "Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence",
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 p16INK4A 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.",
keywords = "8-oxoguanine, DNA damage, p53, Reactive oxygen species (ROS)",
author = "Priyamvada Rai and Onder, {Tamer T.} and Young, {Jennifer J.} and McFaline, {Jose L.} and Bo Pang and Dedon, {Peter C.} and Weinberg, {Robert A.}",
year = "2009",
month = "1",
day = "6",
doi = "10.1073/pnas.0809834106",
language = "English",
volume = "106",
pages = "169--174",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "1",

}

TY - JOUR

T1 - Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence

AU - Rai, Priyamvada

AU - Onder, Tamer T.

AU - Young, Jennifer J.

AU - McFaline, Jose L.

AU - Pang, Bo

AU - Dedon, Peter C.

AU - Weinberg, Robert A.

PY - 2009/1/6

Y1 - 2009/1/6

N2 - 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 p16INK4A 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.

AB - 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 p16INK4A 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.

KW - 8-oxoguanine

KW - DNA damage

KW - p53

KW - Reactive oxygen species (ROS)

UR - http://www.scopus.com/inward/record.url?scp=58549087616&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58549087616&partnerID=8YFLogxK

U2 - 10.1073/pnas.0809834106

DO - 10.1073/pnas.0809834106

M3 - Article

C2 - 19118192

AN - SCOPUS:58549087616

VL - 106

SP - 169

EP - 174

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 1

ER -