A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response
Open accessAbstract
Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.
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?
Many lincRNA-p21 target genes identified in mice are not regulated by p53 in humans.
“Furthermore, many lincRNA-p21 target genes identified in mice125 are not regulated by p53 in humans.53”
From Census and evaluation of p53 target genes (2017) · cites this paper as [125]
Results of experiments that used overexpression or knockdown of miR-34 or lincRNA-p21 barely overlapped with those that used knockout mice.
“For example, results of experiments that used overexpression or knockdown of miR-34 or lincRNA-p21124, 125 barely overlapped with those that used knockout mice.128, 129”
From Census and evaluation of p53 target genes (2017) · cites this paper as [125]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
RETRACTED: hnRNP K: An HDM2 Target and Transcriptional Coactivator of p53 in Response to DNA Damage
Moumen, A., Masterson, P., O'Connor, M. J., & Jackson, S. P. (2005) · Cell · doi:10.1016/j.cell.2005.09.032 · Cited by 350 · see citing works
RetractedSubramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Self-citationLong non-coding RNAs: insights into functions
Mercer, T. R., Dinger, M. E., & Mattick, J. S. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2521 · Cited by 5,654 · see citing works
Evolution and Functions of Long Noncoding RNAs
Ponting, C. P., Oliver, P. L., & Reik, W. (2009) · Cell · doi:10.1016/j.cell.2009.02.006 · Cited by 4,917 · see citing works
Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs
Rinn, J. L., Kertesz, M., Wang, J. K., Squazzo, S. L., Xu, X. H., Brugmann, S. A., Goodnough, L. H., Helms, J. A., Farnham, P., Segal, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.05.022 · Cited by 4,246 · see citing works
Self-citationGenome-wide maps of chromatin state in pluripotent and lineage-committed cells
Mikkelsen, T. S., Ku, M., Jaffe, D. B., Issac, B., Lieberman, E., Giannoukos, G., Alvarez, P., Brockman, W., Kim, T.-K., Koche, R. P., et al. (2007) · Nature · doi:10.1038/nature06008 · Cited by 4,129 · see citing works
Self-citationChromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Guttman, M., Amit, I., Garber, M., French, C., Lin, M. F., Feldser, D., Huarte, M., Zuk, O., Carey, B. W., Cassady, J. P., et al. (2009) · Nature · doi:10.1038/nature07672 · Cited by 4,098 · see citing works
Self-citationKhalil, A. M., Guttman, M., Huarte, M., Garber, M., Raj, A., Rivea Morales, D., Thomas, K., Presser, A., Bernstein, B. E., van Oudenaarden, A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904715106 · Cited by 2,872 · see citing works
Self-citationVienna RNA secondary structure server
Hofacker, I. L. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg599 · Cited by 2,362 · see citing works
Definition of a consensus binding site for p53
El-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W., & Vogelstein, B. (1992) · Nature Genetics · doi:10.1038/ng0492-45 · Cited by 1,985 · see citing works
Transcriptional control of human p53-regulated genes
Riley, T., Sontag, E., Chen, P., & Levine, A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2395 · Cited by 1,921 · see citing works
Wild-type p53 is a cell cycle checkpoint determinant following irradiation.
Kuerbitz, S. J., Plunkett, B., Walsh, W., & Kastan, M. B. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.16.7491 · Cited by 1,837 · see citing works
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · see citing works
Self-citationPolycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome
Zhao, J. C., Sun, B. K., Erwin, J. A., Song, J., & Lee, J. T. (2008) · Science · doi:10.1126/science.1163045 · Cited by 1,580 · see citing works
Radiation-induced cell cycle arrest compromised by p21 deficiency
Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., & Hannon, G. J. (1995) · Nature · doi:10.1038/377552a0 · Cited by 1,242 · cited 1× · see citing works
“Cell-cycle analysis was performed as described (Brugarolas et al., 1995).”
Self-citationPandey, R. R., Mondal, T., Mohammad, F., Enroth, S., Redrup, L., Komorowski, J., Nagano, T., Mancini‐DiNardo, D., & Kanduri, C. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.08.022 · Cited by 1,192 · see citing works
A Global Map of p53 Transcription-Factor Binding Sites in the Human Genome
Wei, C.-L., Wu, Q., Vega, V. B., Chiu, K. P., Ng, P., Zhang, T., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., et al. (2006) · Cell · doi:10.1016/j.cell.2005.10.043 · Cited by 1,141 · see citing works
The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin
Nagano, T., Mitchell, J. A., Sanz, L. A., Pauler, F. M., Ferguson‐Smith, A. C., Feil, R., & Fraser, P. (2008) · Science · doi:10.1126/science.1163802 · Cited by 907 · see citing works
A Transcriptionally Active DNA-Binding Site for Human p53 Protein Complexes
Funk, W. D., Pak, D. T. S., Karas, R. H., Wright, W. E., & Shay, J. W. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.6.2866 · Cited by 732 · see citing works
Functionality or transcriptional noise? Evidence for selection within long noncoding RNAsPreprint
Ponjavic, J., Ponting, C. P., & Lunter, G. A. (2007) · Genome Research · doi:10.1101/gr.6036807 · Cited by 731 · see citing works
Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript
Martianov, I., Ramadass, A., Barros, A. S., Chow, N., & Akoulitchev, A. V. (2007) · Nature · doi:10.1038/nature05519 · Cited by 728 · see citing works
The Genetic Signatures of Noncoding RNAs
Mattick, J. S. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000459 · Cited by 704 · see citing works
The genetics of the p53 pathway, apoptosis and cancer therapy
Vázquez, A., Bond, E. E., Levine, A. J., & Bond, G. L. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2656 · Cited by 674 · see citing works
The P53 pathway: what questions remain to be explored?
Levine, A. J., Hu, W., & Feng, Z. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401910 · Cited by 654 · see citing works
CLIP: A method for identifying protein–RNA interaction sites in living cells
Ule, J., Jensen, K. B., Mele, A., & Darnell, R. B. (2005) · Methods · doi:10.1016/j.ymeth.2005.07.018 · Cited by 597 · see citing works
Identifying novel constrained elements by exploiting biased substitution patterns
Garber, M., Guttman, M., Clamp, M., Zody, M. C., Friedman, N., & Xie, X. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp190 · Cited by 370 · see citing works
Self-citationSchaefer, B. C. (1995) · Analytical Biochemistry · doi:10.1006/abio.1995.1279 · Cited by 322 · see citing works
A strategy for identifying gel-separated proteins in sequence databases by MS alone
Shevchenko, A., Wilm, M. S., Vorm, O., Jensen, O. N., Podtelejnikov, A. V., Neubauer, G., Shevchenko, A. A., Mortensen, P. M., & Mann, M. (1996) · Biochemical Society Transactions · doi:10.1042/bst0240893 · Cited by 248 · see citing works
A Transcriptionally Active DNA-Binding Site for Human p53 Protein Complexes
Funk, W. D., Pak, D. T. S., Karas, R. H., et al. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.6.2866-2871.1992 · Cited by 239 · see citing works
Bull sperm head morphometry related to abnormal chromatin structure and fertility
Sailer, B. L., Jost, L. K., & Evenson, D. P. (1996) · Cytometry · doi:10.1002/(sici)1097-0320(19960601)24:2 · Cited by 148 · see citing works
Kim, K., Choi, J., Heo, K., Kim, H., Levens, D., Kohno, K., Johnson, E. M., Brock, H. W., & An, W. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708205200 · Cited by 116 · see citing works
Grant, G. R., Liu, J., & Stoeckert, C. J. (2005) · Computer applications in the biosciences · doi:10.1093/bioinformatics/bti407 · Cited by 96 · see citing works
Denisenko, O. N., & Bomsztyk, K. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.8.4707 · Cited by 91 · see citing works
Non-coding RNA transcription: turning on neighbours
Carninci, P. (2008) · Nature Cell Biology · doi:10.1038/ncb0908-1023 · Cited by 37 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gene regulation by long non-coding RNAs and its biological functions
Statello, L., Guo, C.-J., Chen, L.-L., & Huarte, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00315-9 · Cited by 4,991 · see citing works
Self-citationLong Noncoding RNAs: Cellular Address Codes in Development and Disease
Batista, P. J., & Chang, H. Y. (2013) · Cell · doi:10.1016/j.cell.2013.02.012 · Cited by 2,531 · see citing works
Long noncoding RNAs: past, present, and future
Kung, J. T. Y., Colognori, D., & Lee, J. T. (2013) · Genetics · doi:10.1534/genetics.112.146704 · Cited by 1,874 · see citing works
The multiple mechanisms that regulate p53 activity and cell fate
Hafner, A., Bulyk, M. L., Jambhekar, A., & Lahav, G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0110-x · Cited by 1,129 · see citing works
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology
Kierans, S. J., & Taylor, C. T. (2021) · The Journal of Physiology · doi:10.1113/jp280572 · Cited by 1,015 · see citing works
Non-coding RNAs as regulators of gene expression and epigenetics
Kaikkonen, M. U., Lam, M. T. Y., & Glass, C. K. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr097 · Cited by 764 · see citing works
Kapusta, A., Kronenberg, Z., Lynch, V. J., Zhuo, X., Ramsay, L., Bourque, G., Yandell, M., & Feschotte, C. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003470 · Cited by 687 · see citing works
Transposable elements reveal a stem cell-specific class of long noncoding RNAs
Kelley, D., & Rinn, J. (2012) · Genome Biology · doi:10.1186/gb-2012-13-11-r107 · Cited by 531 · see citing works
Self-citationeRNAs Are Required for p53-Dependent Enhancer Activity and Gene Transcription
Melo, C. A., Drost, J., Wijchers, P. J., van de Werken, H., de Wit, E., Vrielink, J. A. F. O., Elkon, R., Melo, S. A., Léveillé, N., Kalluri, R., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.11.021 · Cited by 544 · see citing works
Dimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.025 · Cited by 445 · see citing works
Self-citationShamloo, B., & Usluer, S. (2019) · Cancers · doi:10.3390/cancers11081178 · Cited by 336 · see citing works
Gong, C., Li, Z., Ramanujan, K., Clay, I., Zhang, Y., Lemire-Brachat, S., & Glass, D. J. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.05.009 · Cited by 305 · see citing works
Léveillé, N., Melo, C. A., Rooijers, K., Díaz-Lagares, A., Melo, S. A., Korkmaz, G., Lopes, R., Moqadam, F. A., Maia, A. R., Wijchers, P. J., et al. (2015) · Nature Communications · doi:10.1038/ncomms7520 · Cited by 183 · see citing works
Epigenetic regulation: A new frontier for biomedical engineers
Chen, Z., Li, S., Subramaniam, S., Shyy, J. Y.-J., & Chien, S. (2017) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071516-044720 · Cited by 163 · see citing works
The transcription factor p53: Not a repressor, solely an activator.
Fischer, M., Steiner, L., & Engeland, K. (2014) · Cell Cycle · doi:10.4161/15384101.2014.949083 · Cited by 153 · see citing works
Xie, H., Ma, K., Zhang, K., Zhou, J., Li, L., Yang, W., Gong, Y., Cai, L., & Gong, K. (2021) · Cell Death & Disease · doi:10.1038/s41419-020-03229-8 · Cited by 155 · see citing works
Carvajal, L. A., Hamard, P.-J., Tonnessen, C., & Manfredi, J. J. (2012) · Genes & Development · doi:10.1101/gad.184911.111 · Cited by 151 · see citing works
The Toll-like receptor gene family is integrated into human DNA damage and p53 networks
Menendez, D., Shatz, M., Azzam, K., Garantziotis, S., Fessler, M. B., & Resnick, M. A. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001360 · Cited by 148 · see citing works
Nuclear receptor coactivators: structural and functional biochemistry
Bulynko, Y. A., & O’Malley, B. W. (2011) · Biochemistry · doi:10.1021/bi101762x · Cited by 113 · see citing works
Integrative genomic analysis reveals widespread enhancer regulation by p53 in response to DNA damage
Younger, S. T., Kenzelmann-Broz, D., Jung, H., Attardi, L. D., & Rinn, J. L. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv284 · Cited by 99 · see citing works
Self-citationVitamin D receptor, a tumor suppressor in skin
Bikle, D. D. (2015) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2014-0367 · Cited by 101 · see citing works
Involvement of long noncoding RNAs in diseases affecting the central nervous system
Pastori, C., & Wahlestedt, C. (2012) · RNA Biology · doi:10.4161/rna.20482 · Cited by 100 · see citing works
Gao, R., Fang, C., Xu, J., Tan, H., Li, P., & Ma, L. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.01.005 · Cited by 99 · see citing works
Schlereth, K., Heyl, C., Krampitz, A.-M., Mernberger, M., Finkernagel, F., Scharfe, M., Jarek, M., Leich, E., Rosenwald, A., & Stiewe, T. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003726 · Cited by 87 · see citing works
Expanding the p53 regulatory network: LncRNAs take up the challenge
Grossi, E., Sánchez, Y., & Huarte, M. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.07.011 · Cited by 78 · see citing works
Self-citationThe lncRNA Toolkit: Databases and In Silico Tools for lncRNA Analysis
Pinkney, H. R., Wright, B. M., & Diermeier, S. D. (2020) · Non-Coding RNA · doi:10.3390/ncrna6040049 · Cited by 56 · see citing works
An LTR retrotransposon‐derived lncRNA interacts with RNF169 to promote homologous recombination
Deng, B., Xu, W., Wang, Z., Liu, C., Lin, P., Li, B., Huang, Q., Yang, J., Zhou, H., & Qu, L. (2019) · The EMBO Reports · doi:10.15252/embr.201847650 · Cited by 40 · see citing works
The emerging functions of the p53-miRNA network in stem cell biology
Lin, C.-P., Choi, Y. J., Hicks, G. G., & He, L. (2012) · Cell Cycle · doi:10.4161/cc.20207 · Cited by 38 · see citing works
Exploring the read-write genome: mobile DNA and mammalian adaptation
Shapiro, J. A. (2017) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2016.1226748 · Cited by 30 · see citing works
Transcription Blockage by DNA Damage in Nucleotide Excision Repair-Related Neurological Dysfunctions
Kajitani, G. S., Nascimento, L. L. D. S., Neves, M. R. D. C., Leandro, G. D. S., Garcia, C. C. M., & Menck, C. F. M. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.10.009 · Cited by 22 · see citing works
- Authors
- Huarte, M., Guttman, M., Feldser, D., Garber, M., Koziol, M. J., Kenzelmann-Broz, D., Khalil, A. M., Zuk, O., Amit, I., Rabani, M., Attardi, L. D., Regev, A., Lander, E. S., Jacks, T., & Rinn, J. L.
- Affiliations
- Broad Institute (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Stanford Medicine (US)
- Corresponding author
- Huarte, Maite
- Rinn, John L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 142
- Issue
- 3
- Pages
- 409-419
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2956184
- OpenAlex
- W2137840425
- Cited by
- 2,053
- References
- 34
- Citations by year
- 2026: 24 · 2025: 47 · 2024: 64 · 2023: 89 · 2022: 126 · 2021: 141 · 2020: 168 · 2019: 144 · 2018: 154 · 2017: 176 · 2016: 203 · 2015: 193 · 2014: 159 · 2013: 157 · 2012: 121
- FWCI
- 36.28
- 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, 1081 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
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (DP2OD006670, 5r01ca119176-10, DP1OD003958)
- National Cancer Institute (1R01CA119176-01, R01-CA119176)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- lincRNA-p21, p53, transcriptional repression, hnRNP K, p53 response, gene expression regulation, apoptosis, RNA-protein interactions
- MeSH terms
- Animals, Humans, Molecular Sequence Data, Transcription, Genetic, Down-Regulation, Tumor Suppressor Protein p53, Apoptosis, RNA, Untranslated, Heterogeneous-Nuclear Ribonucleoprotein K, Mice
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
