Removing all obstacles: A critical role for p53 in promoting tissue renewal
Open accessAbstract
Defects in DNA repair pathways or exposure to high levels of DNA damaging agents limit the renewal potential of adult tissues and accelerate the development of age-related degenerative pathologies. Many studies suggest these tissue homeostatic defects can result from the accumulation of DNA damage in tissue-specific stem cells. Although maintenance of genome integrity in progenitor cells is required for the renewal of adult tissues, recent studies have highlighted the importance of additional mechanisms that facilitate and direct the process of tissue regeneration. These reports indicate that the p53 tumor suppressor gene maintains adult tissue homeostasis and promotes tissue renewal by suppressing the accumulation of DNA-damaged cells. Without p53, tissue deterioration caused by the elimination of genome maintenance regulators (ATR, Hus1 or Terc) is exacerbated and, in some cases, leads to synthetic lethality at the organismal level. Importantly, the accumulation of highly damaged cells in multiple tissues appears to severely impede regeneration from undamaged progenitors, suggesting that p53-mediated removal of damaged cells is a prerequisite for efficient progenitor driven renewal. These findings argue that tissue homeostasis is governed not only by the intrinsic repopulating potential of competent progenitors, but also by mechanisms that limit the accumulation of defective cells and, thereby, promote compensatory regeneration. As discussed in this review, these findings advance our understanding of mechanisms that counter the effects of DNA damage at the tissue level and have important implications for the development of therapeutic approaches to combating age-related pathologies and p53-deficient malignancies.
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DNA repair is impaired in the absence of functional p53.
“Several studies have demonstrated that DNA repair is impaired in the absence of functional p53 [31].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [31]
The section “p53 is Required for Efficient Tissue Renewal Following Mosaic ATR Deletion” (page unavailable) reports more DNA-damaged cells in p53-null tissues, but attributes their accumulation to less efficient elimination of damaged cells and suggests tolerance or checkpoint defects as possible explanations. Searches for impaired DNA repair and repair capacity without p53 found no passage establishing that DNA repair itself is impaired. (LLM, conf=0.73)
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BackgroundLiao, T., Kaufmann, A., Qian, X., Sangvatanakul, V., Chen, C., Kube, T., Zhang, G.-Y., & Albers, A. (2012) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-012-1311-2 · Cited by 64
A dp53-Dependent Mechanism Involved in Coordinating Tissue Growth in Drosophila
Mesquita, D., Dekanty, A., & Milán, M. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000566 · Cited by 51 · see citing works
“[35]) as well as in response to stress or tissue damage, whereby the”
BackgroundRole of Dietary Antioxidants in p53‐Mediated Cancer Chemoprevention and Tumor Suppression
Merlin, J. P. J., Rupasinghe, H. P. V., Dellaire, G., & Murphy, K. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9924328 · Cited by 68 · see citing works
“In mammalian cells, p53 mediates apoptosis through transcriptional activation of proapoptotic target genes by two major apoptotic pathways: extrinsic pathway, mediated by death domain proteins belonging to the tumor necrosis factor receptor (TNF-R), and intrinsic pathway that monitors the B-cell lymphoma 2 (Bcl-2) fam…”
BackgroundTaylor, J. R., Lehmann, B. D., Chappell, W. H., Abrams, S. L., Steelman, L. S., & McCubrey, J. A. (2011) · Oncotarget · doi:10.18632/oncotarget.315 · Cited by 46 · see citing works
Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing
Pruitt, S. C., Freeland, A. L., Rusiniak, M. E., Kunnev, D., & Cady, G. K. (2013) · Nature Communications · doi:10.1038/ncomms3626 · Cited by 40 · see citing works
Tissue repair and regeneration in Drosophila imaginal discs
Repiso, A., Bergantiños, C., Corominas, M., & Serras, F. (2011) · Development Growth & Differentiation · doi:10.1111/j.1440-169x.2010.01247.x · Cited by 39 · see citing works
“In the absence of p53, tissue deterioration and accumulation of damaged cells impede regeneration by undamaged cells, suggesting that p53-mediated removal of damaged cells is a pre-requisite for efficient progenitor driven renewal (Schoppy et al. 2010).”
BackgroundLin, Y., Murayama, Y., Hashimoto, K., Nakamura, Y., Lin, C.-S., Yokoyama, K. K., & Saito, S. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt447 · Cited by 26 · see citing works
“For example, p53 promotes the maintenance of genome integrity [37] and promotes tissue generation in ATR mutant mice by promoting DNA repair and/or by promoting the death of cells with DNA damage [38]; however, in response to oncogenic stimuli or telomere attrition, p53 depletes stem cells [32,39].”
Backgroundp53 enables metabolic fitness and self-renewal of nephron progenitor cells
Li, Y., Liu, J., Li, W., Brown, A. C., Baddoo, M., Li, M. M., Carroll, T. J., Oxburgh, L. H., Feng, Y., & Saifudeen, Z. R. (2015) · Development · doi:10.1242/dev.111617 · Cited by 37 · see citing works
“*These authors contributed equally to this work ‡Author for correspondence (zubisaif@tulane.edu) D E V E LO P M E N T (Lee et al., 2010; Schoppy et al., 2010; Xu, 2005).”
BackgroundThe role of p21 in regulating mammalian regeneration
Arthur, L. M., & Heber‐Katz, E. (2011) · Stem Cell Research & Therapy · doi:10.1186/scrt71 · Cited by 29 · see citing works
“One study suggests that removal of p53 allows for an accumulation of cells with elevated levels of DNA damage (on a repair-defi cient background mouse), which delays hair follicle renewal and regeneration [80,81].”
BackgroundEpimorphic regeneration in mice is p53-independent
Arthur, L. M., Demarest, R. M., Clark, L. D., Gourevitch, D., Bedelbaeva, K., Anderson, R., Snyder, A. R., Capobianco, A. J., Lieberman, P. M., Feigenbaum, L., et al. (2010) · Cell Cycle · doi:10.4161/cc.9.18.13119 · Cited by 25 · see citing works
Rapamycin induces pluripotent genes associated with avoidance of replicative senescence
Pospelova, T. V., Bykova, T. V., Zubova, S. G., Katolikova, N. V., Yartzeva, N. M., & Pospelov, V. A. (2013) · Cell Cycle · doi:10.4161/cc.27396 · Cited by 25 · see citing works
“Also, mTOR, p53 and other genes are involved in age-related diseases and aging.(73-96) In replicative senescence of rodent cells the relationship between cell cycle arrest and geroconversion is more complex.”
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Nano‐phototherapy: Favorable prospects for cancer treatment
Merlin, J. P. J., Crous, A., & Abrahamse, H. (2023) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1930 · Cited by 23 · see citing works
The p53/Adipose-Tissue/Cancer Nexus
Zwezdaryk, K. J., Sullivan, D. E., & Saifudeen, Z. R. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00457 · Cited by 26 · see citing works
Ubiquitin B in Cervical Cancer: Critical for the Maintenance of Cancer Stem-Like Cell Characters
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Interplay between p53-family, their regulators, and PARPs in DNA repair
Emami, S. (2010) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.gcb.2010.10.002 · Cited by 16 · see citing works
“[2] Schoppy DW, Ruzankina Y, Brown EJ.”
Regulation of kidney development by the Mdm2/Mdm4–p53 axis
El-Dahr, S. S., Hilliard, S. A., & Saifudeen, Z. R. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx005 · Cited by 13 · see citing works
“Besides controlling genes in cell cycle and apoptosis pathways, p53 also regulates cell migration, energy metabolism, differentiation, and renewal (Matoba et al., 2006; Gadea et al., 2007; Lebedeva et al., 2009; Liu et al., 2009; Molchadsky et al., 2010; Schoppy et al., 2010; Hwang et al., 2011).”
BackgroundBiechonski, S., & Milyavsky, M. (2013) · Translational Cancer Research · doi:10.21037/1620 · Cited by 6 · see citing works
“It is becoming increasingly clear that many of the central regulators of the DDR play a key role in the regulation of HSC homeostasis (13,14,25,46-49).”
BackgroundLee, S.-H., Hwang, D., Goo, T.-W., & Yun, E.-Y. (2022) · Developmental and Comparative Immunology · doi:10.1016/j.dci.2022.104539 · Cited by 4
Klos, K. S., Kim, S., & Alexander, C. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049902 · Cited by 3 · see citing works
“These centers may correlate with compensatory regenerative response centers, at sites of damage repair [39].”
BackgroundWang, T., Cui, Y., Liu, P.-G., He, J.-F., & Zhang, Q. (2015) · Folia Morphologica · doi:10.5603/fm.a2018.0067 · Cited by 2
“The study found that p53 positive reaction was widely distributed during the newborn yak, suggesting that p53 was involved in cell migration, metabolism, differentiation, and self-renewal during this period [9,31].”
Tissue-Specific Functions of p53 During Kidney Development
Saifudeen, Z. R. (2017) · Results and problems in cell differentiation · doi:10.1007/978-3-319-51436-9_5 · Cited by 2 · see citing works
“In contrast, another study in mESC showed that p53 induces expression of Wnt ligands and receptors and Lef1 expression and promotes proliferation of self-renewing progenitor populations (Schoppy et al. 2010; Xu 2005; Lee et al. 2010).”
BackgroundResultInfluential
- Authors
- Schoppy, D. W., Ruzankina, Y., & Brown, E. J.
- Affiliations
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- Corresponding author
- Brown, Eric J.
- ORCID
- Brown, Eric J.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2010-04
- Volume
- 9
- Issue
- 7
- Pages
- 1313-1319
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC2980577
- OpenAlex
- W2076689381
- Cited by
- 32
- References
- 70
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 6 · 2012: 4
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Cell Cycle (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (F30AG034027, R01AG027376)
- 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
- p53, tissue renewal, tissue homeostasis, DNA damage, DNA repair, stem cells, genome stability, ATR, Hus1, TERC, synthetic lethality, compensatory regeneration, aging
- MeSH terms
- Animals, DNA Damage, Humans, Neoplasms, Regeneration, Tumor Suppressor Protein p53, Cellular Senescence
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