Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence
Open accessAbstract
Oncogene-induced senescence is characterized by a stable cell growth arrest, thus providing a tumor suppression mechanism. However, the underlying mechanisms for this phenomenon remain unknown. Here, we show that a decrease in deoxyribonucleotide triphosphate (dNTP) levels underlies oncogene-induced stable senescence-associated cell growth arrest. The decrease in dNTP levels is caused by oncogene-induced repression of ribonucleotide reductase subunit M2 (RRM2), a rate-limiting protein in dNTP synthesis. This precedes the senescence-associated cell-cycle exit and coincides with the DNA damage response. Consistently, RRM2 downregulation is both necessary and sufficient for senescence. Strikingly, suppression of nucleotide metabolism by RRM2 repression is also necessary for maintenance of the stable senescence-associated cell growth arrest. Furthermore, RRM2 repression correlates with senescence status in benign nevi and melanoma, and its knockdown drives senescence of melanoma cells. These data reveal the molecular basis whereby the stable growth arrest of oncogene-induced senescence is established and maintained through suppression of nucleotide metabolism.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
RAS activation is linked to loss of intracellular dNTPs through suppression of RRM2 expression.
“RAS activation is also associated with loss of intracellular dNTPs due to suppression of RRM2 expression (Aird et al., 2013).”
From Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis (2021) · cites this paper as Aird et al., 2013
Oncogenes may induce associated DNA damage by transcriptionally downregulating ribonucleotide reductase M2 (RRM2), a regulator of the nucleotide metabolic pathway that ultimately affects the metabolism and decreases dNTP levels.
“Oncogenes may induce associated DNA damage by transcriptionally downregulating ribonucleotide reductase M2 (RRM2), a regulator of the nucleotide metabolic pathway that ultimately affects the metabolism and decreases dNTP levels [119].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [119]
During OIS, fatty acid metabolism is altered, glucose consumption is enhanced, and utilization of pyruvate in the tricarboxylic acid cycle and nucleotide deficiency are increased.
“Moreover, during OIS, fatty acid metabolism is altered, glucose consumption is enhanced, and the utilization of pyruvate in the tricarboxylic acid cycle and nucleotide deficiency are increased [119,216,217,218,219].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [119]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 52 · Cited by 285
Research works printed but not linked: 1
- Kuilman T Michaloglou C Mooi WJ Peeper DS 2010 The essence of senescence Genes Dev 24 2463 2479 21078816 PMC2975923
- Authors
- Aird, K. M., Zhang, G., Li, H., Tu, Z., Bitler, B. G., Garipov, A., Wu, H., Wei, Z., Wagner, S. N., Herlyn, M., & Zhang, R.
- Affiliations
- The Wistar Institute (US)
- Fox Chase Cancer Center (US)
- New Jersey Institute of Technology (US)
- Austrian Academy of Sciences (AT)
- Corresponding author
- Zhang, Rugang
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 3
- Issue
- 4
- Pages
- 1252-1265
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3840499
- OpenAlex
- W2141689006
- Cited by
- 285
- References
- 52
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 18 · 2023: 18 · 2022: 33 · 2021: 26 · 2020: 26 · 2019: 19 · 2018: 16 · 2017: 19 · 2016: 32 · 2015: 20 · 2014: 21 · 2013: 5
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ovarian Cancer Research Fund
- Austrian Science Fund
- National Institutes of Health
- National Cancer Institute (R01CA047159, CA010815, R01CA076674, T32CA9171-35, R01CA160331, T32CA009171, P30CA010815)
- Ovarian Cancer Academy
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- oncogene-induced senescence, nucleotide metabolism, RRM2, DNA damage response, cell cycle arrest, melanoma, benign nevi, tumor suppression
- MeSH terms
- Cell Line, DNA Repair, Humans, Nucleosides, Oncogenes, Promoter Regions, Genetic, Purine Nucleotides, Pyrimidine Nucleotides, Ribonucleoside Diphosphate Reductase, Down-Regulation, Cellular Senescence, ras Proteins, RNA Interference, RNA, Small Interfering, Proto-Oncogene Proteins B-raf, E2F7 Transcription Factor, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
