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 language | English |
|---|---|
| Pages (from-to) | 169-174 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 106 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 6 2009 |
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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 journal › Article
}
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 -