The DOI matches its Crossref record; 59 of the 60 references it cites were found in a registry or an index.
p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression
Open accessPublished version of a preprint
Abstract
Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.
Overview
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
Verification
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?
In the citing paper
“Links between IL-1 signalling and p53 have been reported in the context of tumour cells 68,69 , and the cGAS-STING axis is increasingly linked to DNA damage 70 , although the exact triggers of this pathway in the context of AAV-mediated CNS transduction remain to be defined.”
From AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain (2025) · cites this paper as [70]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
Sun, L., Wu, J., Du, F., Chen, X., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1232458 · Cited by 4,996
Seth, R. B., Sun, L., Ea, C.-K., & Chen, Z. J. (2005) · Cell · doi:10.1016/j.cell.2005.08.012 · Cited by 3,329
IKKε and TBK1 are essential components of the IRF3 signaling pathway
Fitzgerald, K. A., McWhirter, S. M., Faia, K. L., Rowe, D. C., Latz, E., Golenbock, D. T., Coyle, A. J., Liao, S.-M., & Maniatis, T. (2003) · Nature Immunology · doi:10.1038/ni921 · Cited by 2,680
Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., & Chen, Z. J. (2012) · Science · doi:10.1126/science.1229963 · Cited by 2,628
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction
Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K. J., Takeuchi, O., & Akira, S. (2005) · Nature Immunology · doi:10.1038/ni1243 · Cited by 2,562
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
T antigen is bound to a host protein in SY40-transformed cells
Lane, D. P., & Crawford, L. V. (1979) · Nature · doi:10.1038/278261a0 · Cited by 2,456
Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus
Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., & Tschopp, J. (2005) · Nature · doi:10.1038/nature04193 · Cited by 2,401
Deng, L., Liang, H., Xu, M., Yang, X., Burnette, B., Arina, A., Li, X.-D., Mauceri, H., Beckett, M., Darga, T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.019 · Cited by 2,182
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., et al. (2015) · Science · doi:10.1126/science.aaa2630 · Cited by 1,927
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors
Woo, S.-R., Fuertes, M. B., Corrales, L., Spranger, S., Furdyna, M. J., Leung, M. Y. K., Duggan, R., Wang, Y., Barber, G. N., Fitzgerald, K. A., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.017 · Cited by 1,917
Linzer, D. I. H., & Levine, A. J. (1979) · Cell · doi:10.1016/0092-8674(79)90293-9 · Cited by 1,814
Human Cells Lacking mtDNA: Repopulation with Exogenous Mitochondria by Complementation
King, M. P., & Attardi, G. M. (1989) · Science · doi:10.1126/science.2814477 · Cited by 1,685
STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway
Tanaka, Y., & Chen, Z. J. (2012) · Science Signaling · doi:10.1126/scisignal.2002521 · Cited by 1,359
Cytoplasmic chromatin triggers inflammation in senescence and cancer
Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017) · Nature · doi:10.1038/nature24050 · Cited by 1,335
The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer
Li, T., & Chen, Z. J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180139 · Cited by 1,293
Trex1 prevents cell-intrinsic initiation of autoimmunity
Stetson, D. B., Ko, J. S., Heidmann, T., & Medzhitov, R. (2008) · Cell · doi:10.1016/j.cell.2008.06.032 · Cited by 1,280
The codon 72 polymorphic variants of p53 have markedly different apoptotic potential
Dumont, P., Leu, J. I.-J., Pietra, A. D., George, D. L., & Murphy, M. E. (2003) · Nature Genetics · doi:10.1038/ng1093 · Cited by 1,269
cGAS in action: Expanding roles in immunity and inflammation
Ablasser, A., & Chen, Z. J. (2019) · Science · doi:10.1126/science.aat8657 · Cited by 1,077
cGAS is essential for cellular senescence
Yang, H., Wang, H., Ren, J., Chen, Q., & Chen, Z. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705499114 · Cited by 1,009
Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., Black, D. N., van Bokhoven, H., Brunner, H. G., Hamel, B. C. J., et al. (2006) · Nature Genetics · doi:10.1038/ng1845 · Cited by 906
DeLeo, A. B., Jay, G. D., Appella, E., DuBois, G. C., Law, L. W., & Old, L. J. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.5.2420 · Cited by 721
Xia, T., Konno, H., Ahn, J., & Barber, G. N. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.029 · Cited by 589
Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease
Yang, Y., Lindahl, T. L., & Barnes, D. E. (2007) · Cell · doi:10.1016/j.cell.2007.10.017 · Cited by 574
McWhirter, S. M., Fitzgerald, K. A., Rosains, J., Rowe, D. C., Golenbock, D. T., & Maniatis, T. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2237236100 · Cited by 542
Gall, A., Treuting, P., Elkon, K. B., Loo, Y.-M., Gale, M., Barber, G. N., & Stetson, D. B. (2012) · Immunity · doi:10.1016/j.immuni.2011.11.018 · Cited by 510
Signalling strength determines proapoptotic functions of STING
Gulen, M. F., Koch, U., Haag, S. M., Schuler, F., Apetoh, L., Villunger, A., Radtke, F., & Ablasser, A. (2017) · Nature Communications · doi:10.1038/s41467-017-00573-w · Cited by 505
DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway
Lau, L., Gray, E. E., Brunette, R. L., & Stetson, D. B. (2015) · Science · doi:10.1126/science.aab3291 · Cited by 466
Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis
Xia, T., Konno, H., & Barber, G. N. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1404 · Cited by 397
Gray, E. E., Treuting, P. M., Woodward, J. J., & Stetson, D. B. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500969 · Cited by 384
Morita, M., Stamp, G., Robins, P., Dulic, A., Rosewell, I. R., Hrivnak, G., Daly, G., Lindahl, T. L., & Barnes, D. E. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.15.6719-6727.2004 · Cited by 380
Regulation of cellular senescence by p53
Itahana, K., Dimri, G., & Campisi, J. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02228.x · Cited by 365
Kress, M., May, E., Cassingena, R., & May, P. (1979) · Journal of Virology · doi:10.1128/jvi.31.2.472-483.1979 · Cited by 359
Mutant p53 Suppresses Innate Immune Signaling to Promote Tumorigenesis
Ghosh, M., Saha, S., Bettke, J. A., Nagar, R., Parrales, A., Iwakuma, T., van der Velden, A. W. M., & Martinez, L. A. (2020) · Cancer Cell · doi:10.1016/j.ccell.2021.01.003 · Cited by 355
Self-citationTakahashi, A., Loo, T. M., Okada, R., Kamachi, F., Watanabe, Y., Wakita, M., Watanabe, S., Kawamoto, S., Miyata, K., Barber, G. N., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03555-8 · Cited by 350
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses
Ma, Z., Jacobs, S. R., West, J. A., Stopford, C. M., Zhang, Z., Davis, Z. H., Barber, G. N., Glaunsinger, B. A., Dittmer, D. P., & Damania, B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503831112 · Cited by 318
Trim24 targets endogenous p53 for degradation
Allton, K., Jain, A. K., Herz, H.-M., Tsai, W.-W., Jung, S. Y., Qin, J., Bergmann, A., Johnson, R. L., & Barton, M. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813177106 · Cited by 292
Konno, H., Yamauchi, S., Berglund, A., Putney, R. M., Mulé, J. J., & Barber, G. N. (2018) · Oncogene · doi:10.1038/s41388-017-0120-0 · Cited by 281
Mazur, D. J., & Perrino, F. W. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19655 · Cited by 272
TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner
Ablasser, A., Hemmerling, I., Schmid-Burgk, J. L., Behrendt, R., Roers, A., & Hornung, V. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400737 · Cited by 254
Transcriptional role of p53 in interferon-mediated antiviral immunity
Muñoz‐Fontela, C., Macip, S., Martínez‐Sobrido, L., Brown, L. M., Ashour, J., García‐Sastre, A., Lee, S. W., & Aaronson, S. A. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20080383 · Cited by 245
DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway
Parrales, A., Ranjan, A., Iyer, S. V., Padhyé, S., Weir, S. J., Roy, A., & Iwakuma, T. (2016) · Nature Cell Biology · doi:10.1038/ncb3427 · Cited by 239
Cancer-Specific Loss of p53 Leads to a Modulation of Myeloid and T Cell Responses
Blagih, J., Zani, F., Chakravarty, P., Hennequart, M., Pilley, S. E., Hobor, S., Hock, A. K., Walton, J. B., Morton, J. P., Gronroos, E. C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.028 · Cited by 175
Zhou, X., Singh, M., Sanz Santos, G., Guerlavais, V., Carvajal, L. A., Aivado, M., Zhan, Y., Oliveira, M. M. S., Westerberg, L. S., Annis, D. A., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1741 · Cited by 169
Guo, G., Yu, M., Xiao, W., Celis, E., & Cui, Y. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2832 · Cited by 168
de Queiroz, N. M. G. P., Xia, T., Konno, H., & Barber, G. N. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0504 · Cited by 144
Jain, A. K., Allton, K. L., Duncan, A. D., & Barton, M. C. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01705-12 · Cited by 103
Hasan, M., Gonugunta, V. K., Dobbs, N., Ali, A., Palchik, G. A., Calvaruso, M. A., DeBerardinis, R. J., & Yan, N. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611113114 · Cited by 102
cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model
Xiao, N., Wei, J., Xu, S., Du, H., Huang, M., Zhang, S., Ye, W., Sun, L., & Chen, Q. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.03.001 · Cited by 99
P53 and The Immune Response: 40 Years of Exploration—A Plan for the Future
Levine, A. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020541 · Cited by 97
Structure and Expression of the TREX1 and TREX2 3′→5′ Exonuclease Genes
Mazur, D. J., & Perrino, F. W. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010051200 · Cited by 73
TREX1 as a Novel Immunotherapeutic Target
Hemphill, W. O., Simpson, S. R., Liu, M., Salsbury, F. R., Hollis, T., Grayson, J. M., & Perrino, F. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.660184 · Cited by 72
Brucet, M., Querol‐Audí, J., Serra, M., Ramirez‐Espain, X., Bertlik, K., Ruiz, L., Lloberas, J., Macías, M. J., Fita, I., & Celada, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700236200 · Cited by 56
TREX1 – Apex predator of cytosolic DNA metabolism
Simpson, S. R., Hemphill, W. O., Hudson, T., & Perrino, F. W. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102894 · Cited by 54
Long story short: p53 mediates innate immunity
Miciak, J. J., & Bunz, F. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.03.001 · Cited by 49
The TREX1 C-terminal Region Controls Cellular Localization through Ubiquitination
Orebaugh, C. D., Fye, J. M., Harvey, S. E., Hollis, T., Wilkinson, J. C., & Perrino, F. W. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.503391 · Cited by 43
Viral and cellular oncogenes promote immune evasion
Roetman, J. J., Apostolova, M. K. I., & Philip, M. (2022) · Oncogene · doi:10.1038/s41388-021-02145-1 · Cited by 32
Cited by
Sorted by citations
Understanding the complexity of p53 in a new era of tumor suppression
Liu, Y., Su, Z., Tavana, O., & Gu, W. J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.009 · Cited by 538
Mitochondria-associated programmed cell death as a therapeutic target for age-related disease
Nguyễn, T. T., Wei, S., Nguyen, T. H., Jo, Y., Zhang, Y., Park, W., Gariani, K., Oh, C., Kim, H. H., Ha, K., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01046-5 · Cited by 351
Translating p53-based therapies for cancer into the clinic
Peuget, S., Zhou, X., & Selivanova, G. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-023-00658-3 · Cited by 208
The balance of STING signaling orchestrates immunity in cancer
Lanng, K. R. B., Lauridsen, E. L., & Jakobsen, M. R. (2024) · Nature Immunology · doi:10.1038/s41590-024-01872-3 · Cited by 179
“The degradation of TREX1 mediated by p53, thus increases cytosolic DNA accumulation and STING activation 45 .”
TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
Tani, T., Mathsyaraja, H., Campisi, M., Li, Z., Haratani, K., Fahey, C. G., Ota, K., Mahadevan, N. R., Shi, Y., Saito, S., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0700 · Cited by 116
Metadata
- Authors
- Ghosh, M., Saha, S., Li, J., Montrose, D. C., & Martinez, L. A.
- Affiliations
- Stony Brook University (US)
- Stony Brook Medicine (US)
- Corresponding author
- Martinez, Luis A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2023-01
- Volume
- 83
- Issue
- 2
- Pages
- 266-280.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC9993620
- OpenAlex
- W4315705275
- Cited by
- 166
- References
- 60
- Citations by year
- 2026: 48 · 2025: 54 · 2024: 37 · 2023: 27
- FWCI
- 18.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stony Brook University
- National Institutes of Health
- National Cancer Institute (K22CA226033, R01CA166974)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TP53, p53, cGAS-STING pathway, cytosolic DNA sensing, TRIM24, type I interferon, IFNB1, tumor suppression, innate immunity, double-stranded DNA, ubiquitin ligase
- MeSH terms
- STING Protein, DNA, Immunity, Innate, Interferon Type I, Membrane Proteins, Nucleotidyltransferases, Signal Transduction, Tumor Suppressor Protein p53
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
