DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions.
Open accessAbstract
DNA damage leads to a halt in proliferation owing to apoptosis or senescence, which prevents transmission of DNA alterations. This cellular response depends on the tumor suppressor p53 and functions as a powerful barrier to tumor development. Adult stem cells are resistant to DNA damage-induced apoptosis or senescence, however, and how they execute this response and suppress tumorigenesis is unknown. We show that irradiation of hematopoietic and mammary stem cells up-regulates the cell cycle inhibitor p21, a known target of p53, which prevents p53 activation and inhibits p53 basal activity, impeding apoptosis and leading to cell cycle entry and symmetric self-renewing divisions. p21 also activates DNA repair, limiting DNA damage accumulation and self-renewal exhaustion. Stem cells with moderate DNA damage and diminished self-renewal persist after irradiation, however. These findings suggest that stem cells have evolved a unique, p21-dependent response to DNA damage that leads to their immediate expansion and limits their long-term survival.
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p21 upregulation protected HSCs against IR by limiting IR-induced DNA damage and p53 activation and by promoting HSC cell cycle entry and self-renewing expansion.
“p21 upregulation actually protected HSCs against IR by limiting IR-induced DNA damage and p53 activation and by promoting HSC cell cycle entry and self-renewing expansion, suggesting that p21 and p16 may have opposite effects on IR-induced HSC senescence.46-48”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [46]
Cites
Hematopoiesis: An Evolving Paradigm for Stem Cell Biology
Orkin, S. H., & Zon, L. I. (2008) · Cell · doi:10.1016/j.cell.2008.01.025 · Cited by 2,570 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
Hematopoietic Stem Cell Quiescence Maintained by p21 <sup>cip1/waf1</sup>
Cheng, T., Rodrigues, N., Shen, H., Yang, Y.-G., Dombkowski, D., Sykes, M., & Scadden, D. T. (2000) · Science · doi:10.1126/science.287.5459.1804 · Cited by 1,339 · see citing works
Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age
Rossi, D. J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., & Weissman, I. L. (2007) · Nature · doi:10.1038/nature05862 · Cited by 1,115 · see citing works
How stem cells age and why this makes us grow old
Sharpless, N. E., & DePinho, R. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2241 · Cited by 843 · see citing works
The Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem Cells
Cicalese, A., Bonizzi, G., Pasi, C. E., Faretta, M., Ronzoni, S., Giulini, B., Brisken, C., Minucci, S., Fiore, P. P. D., & Pelicci, P. G. (2009) · Cell · doi:10.1016/j.cell.2009.06.048 · Cited by 695 · see citing works
Self-citationTumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 604 · see citing works
Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis
Mohrin, M., Bourke, E., Alexander, D., Warr, M. R., Barry-Holson, K., Le Beau, M. M., Morrison, C. G., & Passegué, E. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.06.014 · Cited by 599 · see citing works
Merritt, A. J., Potten, C. S., Kemp, C. J., Hickman, J. A., Balmain, A., Lane, D. P., & Hall, P. A. (1994) · PubMed · Cited by 560 · see citing works
DNA repair is limiting for haematopoietic stem cells during ageing
Nijnik, A., Woodbine, L., Marchetti, C., Dawson, S., Lambe, T., Liu, C., Rodrigues, N. P., Crockford, T. L., Cabuy, E., Vindigni, A., et al. (2007) · Nature · doi:10.1038/nature05875 · Cited by 518 · see citing works
Weissman, I. L., & Shizuru, J. A. (2008) · Blood · doi:10.1182/blood-2008-08-078220 · Cited by 478 · see citing works
Multiple roles of the cell cycle inhibitor p21CDKN1A in the DNA damage response
Cazzalini, O., Scovassi, A. I., Savio, M., Stivala, L. A., & Prosperi, E. (2010) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2010.01.009 · Cited by 430 · see citing works
Davis, R. L., & Turner, D. L. (2001) · Oncogene · doi:10.1038/sj.onc.1205094 · Cited by 387 · see citing works
DNA-Damage Response in Tissue-Specific and Cancer Stem Cells
Blanpain, C., Mohrin, M., Sotiropoulou, P. A., & Passegue, E. A. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.012 · Cited by 350 · see citing works
Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging
Rübe, C. E., Fricke, A., Widmann, T. A., Fürst, T., Madry, H., Pfreundschuh, M., & Rübe, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017487 · Cited by 307 · see citing works
Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells
Viale, A., Franco, F., Orleth, A., Cambiaghi, V., Giuliani, V., Bossi, D., Ronchini, C., Ronzoni, S., Muradore, I., Monestiroli, S., et al. (2008) · Nature · doi:10.1038/nature07618 · Cited by 303 · see citing works
Self-citationMilyavsky, M., Gan, O. I., Trottier, M., Komosa, M., Tabach, O., Notta, F., Lechman, E. R., Hermans, K. G., Eppert, K., Konovalova, Z., et al. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.05.016 · Cited by 280 · see citing works
Sotiropoulou, P. A., Candi, A., Mascré, G., Clercq, S. D., Youssef, K. K., Lapouge, G., Dahl, E., Semeraro, C., Denecker, G., Marine, J., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2059 · Cited by 245 · see citing works
PUMA Regulates Intestinal Progenitor Cell Radiosensitivity and Gastrointestinal Syndrome
Qiu, W., Carson-Walter, E. B., Liu, H., Epperly, M. W., Greenberger, J. S., Zambetti, G. P., Zhang, L., & Yu, J. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.03.009 · Cited by 223 · see citing works
Delayed kinetics of DNA double‐strand break processing in normal and pathological aging
Sedelnikova, O. A., Horikawa, I., Redon, C., Nakamura, A., Zimonjic, D. B., Popescu, N. C., & Bonner, W. M. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2007.00354.x · Cited by 207 · see citing works
p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2.
Aliouat-Denis, C.-M., Dendouga, N., Van den Wyngaert, I., Goehlmann, H., Steller, U., van de Weyer, I., Van Slycken, N., Andries, L., Kass, S., Luyten, W., et al. (2005) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-05-0121 · Cited by 177 · see citing works
Rossi, D. J., Seita, J., Czechowicz, A. D., Bhattacharya, D., Bryder, D., & Weissman, I. L. (2007) · Cell Cycle · doi:10.4161/cc.6.19.4759 · Cited by 175 · see citing works
DNA Damage-Dependent Cell Cycle Checkpoints and Genomic Stability
Ishikawa, K., Ishii, H., & Saito, T. (2006) · DNA and Cell Biology · doi:10.1089/dna.2006.25.406 · Cited by 154 · see citing works
A Limited Role for p21Cip1/Waf1 in Maintaining Normal Hematopoietic Stem Cell Functioning
van Os, R. P., Kamminga, L. M., Ausema, A., Bystrykh, L. V., Draijer, D. P., van Pelt, K., Dontje, B., & de Haan, G. (2006) · Stem Cells · doi:10.1634/stemcells.2006-0631 · Cited by 118 · see citing works
Xu, H., Balakrishnan, K., Malaterre, J., Beasley, M. D., Yan, Y., Essers, J., Appeldoorn, E., Thomaszewski, J. M., Vazquez, M., Verschoor, S., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012112 · Cited by 101 · see citing works
p53 Deficiency Sensitizes Clonogenic Cells to Irradiation in the Large but Not the Small Intestine
Hendry, J. H., Cai, W. B., Roberts, S. A., & Potten, C. S. (1997) · Radiation Research · doi:10.2307/3579610 · Cited by 54 · see citing works
Differential DNA Damage Response in Stem and Progenitor Cells
Seita, J., Rossi, D. J., & Weissman, I. L. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.07.006 · Cited by 51 · see citing works
Stem Cells and DNA Damage: Persist or Perish?
Lane, A. A., & Scadden, D. T. (2010) · Cell · doi:10.1016/j.cell.2010.07.030 · Cited by 30 · see citing works
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Vitale, I., Manic, G., De Maria, R., Kroemer, G., & Galluzzi, L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.006 · Cited by 361 · see citing works
Impact of genomic damage and ageing on stem cell function
Behrens, A., van Deursen, J. M., Rudolph, K. L., & Schumacher, B. (2014) · Nature Cell Biology · doi:10.1038/ncb2928 · Cited by 207 · see citing works
Shao, L., Feng, W., Li, H., Gardner, D., Luo, Y., Wang, Y., Liu, L., Meng, A., Sharpless, N. E., & Zhou, D. (2014) · Blood · doi:10.1182/blood-2013-07-515619 · Cited by 165 · see citing works
Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome
Colla, S., Ong, D. S. T., Ogoti, Y., Marchesini, M., Mistry, N. A., Clise-Dwyer, K., Ang, S. A., Storti, P., Viale, A., Giuliani, N., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.007 · Cited by 105 · see citing works
Self-citationArai, F., Stumpf, P. S., Ikushima, Y. M., Hosokawa, K., Roch, A., Lutolf, M. P., Suda, T., & MacArthur, B. D. (2020) · Cell Systems · doi:10.1016/j.cels.2020.11.004 · Cited by 19 · see citing works
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Garyn, C. M., Bover, O., Murray, J. W., Ma, J., Salas-Briceno, K., Ross, S. R., & Snoeck, H.-W. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114388 · Cited by 14 · see citing works
- Authors
- Insinga, A., Cicalese, A., Faretta, M., Gallo, B., Albano, L., Ronzoni, S., Furia, L., Viale, A., & Pelicci, P. G.
- Affiliations
- European Institute of Oncology (IT)
- University of Milan (IT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-02-15
- Volume
- 110
- Issue
- 10
- Pages
- 3931-3936
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3593901
- OpenAlex
- W2011942829
- Cited by
- 140
- References
- 28
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 3 · 2020: 14 · 2019: 13 · 2018: 7 · 2017: 11 · 2016: 14 · 2015: 13 · 2014: 16 · 2013: 15
- FWCI
- 10.35
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- DNA damage response, adult stem cells, p21, p53, hematopoietic stem cells, mammary stem cells, irradiation, apoptosis, senescence, DNA repair, cell cycle entry, tumor suppression
- MeSH terms
- Animals, Cell Division, DNA Damage, DNA Repair, Female, Hematopoietic Stem Cells, Mammary Glands, Animal, Mice, Inbred C57BL, Up-Regulation, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p21, Mice, Adult Stem Cells, Mice, 129 Strain, Cell Cycle Checkpoints
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