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Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Abstract
The 'ataxia telangiectasia mutated' (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress. Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia-telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma. Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-/- mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm-/- HSCs, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a)-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-/- HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress.
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In the citing paper
“other studies have shown the potential of antioxidants to improve the function of old HSCs (76,96).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [96]
In the citing paper
“in HSCs and neural stem cells (NSCs) of mice, excessive cellular ROS concentrations lead to abnormal proliferation, malignancy and compromised stem cell self-renewal11–14”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“experimentally induced genetic disruption of DDR pathways in mice also produces cell-autonomous defects in HSC function, as assayed by in vivo hematopoietic reconstitution and in vitro colony forming assays11,36,52,53.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“age-dependent alterations in regulation of SOD2 by FoxO3 and the DNA damage sensing serine/threonine protein kinase ATM (ataxia-telangiectasia mutated) have been shown to contribute to loss of HSC function with aging11,16, 24.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“Another potential function for ATM in suppressing progeroid phenotypes may be related to reported ATM functions in regulating intracellular ROS levels and sensitivity to these molecules (Barzilai et al., 2002; Ito et al., 2004”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ito et al., 2004
In the citing paper
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.20,21”
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 [20]
In the citing paper
“Furthermore, mutation of the ataxia telangiectasia mutated (ATM) gene also results in upregulation of p16 and Arf in HSCs.”
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 [20]
In the citing paper
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
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 [20]
In the citing paper
“mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment 34”
From The common biology of cancer and ageing (2007) · cites this paper as [34]
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“In fact, mouse models with defective genome maintenance mechanisms suffer from severe hematopoietic phenotypes and hematopoietic stem cell (HSC) deficiencies (Ito et al., 2004; Nijnik et al., 2007; Rossi et al., 2007).”
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“Among their evolved adaptations are elaborate cellular protective programs that ensure stem cell integrity, tissue homeostasis, and organismal survival (Biteau, Hochmuth & Jasper, 2008; Brown et al., 2013; Ito et al., 2004; Rando, 2006; Renault et al., 2009; Rossi, Jamieson & Weissman, 2008; Rossi et al., 2007; Sahin…”
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“The initial realization of the ability of elevated levels of ROS to limit HSC self-renewal came from the observation that mice lacking the ataxia telangiectasia mutated (Atm) gene develop early-onset bone marrow failure that correlated with increased ROS abundance (Ito et al., 2004).”
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“8 Selenoproteins number 25 in humans and antioxidant members comprise (1) the glutathione peroxidase (GPx) enzymes that reduce hydrogen- and lipid-peroxides, (2) thioredoxin reductase (TR) that has an essential role in maintaining thioredoxin in a reduced and active state, (3) methionine sulphoxide reductase that repa…”
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“…to ROS and many of these pathologies can be reversed by the addition of antioxidants, highlighting the important role of ATM in regulating redoxhomeostasis (Ito et al., 2004; Reliene and Schiestl, 2006, 2007; Reliene et al., 2008; Freund et al., 2011; Okuno et al., 2012; D’Souza et al., 2013).”
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BackgroundInfluentialMetabolic Regulation of Hematopoietic Stem Cells
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Wang, Y., Liu, L., & Zhou, D. (2011) · Radiation Research · doi:10.1667/rr2727.1 · Cited by 67
Stem cells in squamous head and neck cancer
Albers, A. E., Chen, C., Köberle, B., Qian, X., Klußmann, J. P., Wollenberg, B., & Kaufmann, A. M. (2011) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.03.004 · Cited by 71
“It was found that hematopoietic stem cells and mammary epithelial stem cells contained ROS at lower levels than their mature progeny cells [145,146].”
BackgroundLiu, L., Inoki, A., Fan, K., Mao, F., Shi, G., Jin, X., Zhao, M., Ney, G. M., Jones, M., Sun, S., et al. (2020) · Blood · doi:10.1182/blood.2020007975 · Cited by 62
DNA repair as a shared hallmark in cancer and ageing
Clarke, T. L., & Mostoslavsky, R. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13285 · Cited by 74
Macleod, K. F. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2504 · Cited by 68
Muthná, D., Soukup, T., Vávrová, J., Mokrý, J., Ćmielová, J., Víšek, B., Mrkvicová, A., Havelek, R., Suchánek, J., Filip, S., et al. (2010) · Stem Cells and Development · doi:10.1089/scd.2009.0449 · Cited by 66
“In ATM − / − mice, elevation of ROS levels induces HSC-specifi c phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence [ 13 , 14 ].”
Kim, S., Noguera, J. C., Morales, J., & Velando, A. (2010) · Evolutionary Ecology · doi:10.1007/s10682-010-9426-x · Cited by 65
“Recent molecular studies have shown that resistance to a ROSinduced hemolysis and regulations of postnatal growth rates possibly have genetic bases in mammals (Ito et al. 2004; Lui et al. 2008).”
BackgroundSmall molecule–based reversible reprogramming of cellular lifespan
Won, J., Kim, M. K., Kim, N., Ahn, J. H., Lee, W. G., Kim, S. S., Chang, K.-Y., Yi, Y.-W., & Kim, T. K. (2006) · Nature Chemical Biology · doi:10.1038/nchembio800 · Cited by 68
“Abrogation of the ATM gene, as in individuals with ataxia telangiectasia, leads to accelerated senescence, which is thought to be associated with telomere instability or elevated reactive oxygen species (ROS)-induced DNA damag”
BackgroundRetractedRasheed, N., Wang, X., Niu, Q., Yeh, J. K., & Li, B. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl116 · Cited by 66
“An aberration in oxidative stress response was found to affect hematopoietic stem cell renewal in Atm mice (16).”
BackgroundWnt5a Regulates Hematopoietic Stem Cell Proliferation and Repopulation Through the Ryk Receptor
Povinelli, B. J., & Nemeth, M. J. (2013) · Stem Cells · doi:10.1002/stem.1513 · Cited by 67
Stringari, C., Sierra, R., Donovan, P. J., & Gratton, E. (2012) · Journal of Biomedical Optics · doi:10.1117/1.jbo.17.4.046012 · Cited by 66
Maintenance of genomic integrity in hematopoietic stem cells
Naka, K., & Hirao, A. (2011) · International Journal of Hematology · doi:10.1007/s12185-011-0793-z · Cited by 68
“Studies of Atm-deficient mice have demonstrated that Atm kinase controls the selfrenewal capacity of HSCs [ 11 ].”
BackgroundSelf-citationATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses
Berger, N. D., Stanley, F. K. T., Moore, S., & Goodarzi, A. A. (2017) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2016.0283 · Cited by 65
Hu, L., Yin, X., Zhang, Y., Pang, A., Xie, X., Yang, S., Zhu, C., Li, Y., Zhang, B., Huang, Y., et al. (2021) · Blood · doi:10.1182/blood.2020007362 · Cited by 65
Nitta, E., Yamashita, M., Hosokawa, K., Xian, M., Takubo, K., Arai, F., Nakada, S., & Suda, T. (2011) · Blood · doi:10.1182/blood-2010-08-297390 · Cited by 64
Self-citationThe axis of mTOR-mitochondria-ROS and stemness of the hematopoietic stem cells
Chen, C., Liu, Y., Liu, Y., & Zheng, P. (2009) · Cell Cycle · doi:10.4161/cc.8.8.8139 · Cited by 67
Baris, O. R., Klose, A., Kloepper, J. E., Weiland, D., Neuhaus, J., Schauen, M., Wille, A., Müller, A., Merkwirth, C., Langer, T., et al. (2011) · Stem Cells · doi:10.1002/stem.695 · Cited by 66
Resilient and resourceful: Genome maintenance strategies in hematopoietic stem cells
Bakker, S. T., & Passegue, E. A. (2013) · Experimental Hematology · doi:10.1016/j.exphem.2013.09.007 · Cited by 67
“Atm-deficient mice display a contraction of the HSC pool with decreased self-renewal capacity and loss of quiescence, which ultimately leads to HSC exhaustion associated with the development of age-associated BMF syndrome and increased p16/p19 expression [35,36].”
BackgroundO’Keefe, L. V., Colella, A. D., Dayan, S., Chen, Q., Choo, A., Jacob, R. P., Price, G. R., Venter, D. J., & Richards, R. I. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq495 · Cited by 66
“Levels of ROS are known to limit the selfrenewal of stem cells (50) which are consistent with mounting evidence that breast cancer cells derive from stem cells (51) and are therefore likely to retain some of their properties.”
BackgroundRamakrishnan, V., Xu, B., Akers, J. C., Nguyen, T. P., Ma, J., Dhawan, S., Ning, J., Mao, Y. Q., Hua, W., Kokkoli, E., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102736 · Cited by 68
“However, induction of the CSC state also increases glioblastoma resistance to DNA damaging agents through MGMT-independent mechanisms [45,46].”
BackgroundMitochondrial Microheteroplasmy and a Theory of Aging and Age-Related Disease
Smigrodzki, R. M., & Khan, S. M. (2005) · Rejuvenation Research · doi:10.1089/rej.2005.8.172 · Cited by 62
Role of the polycomb group proteins in hematopoietic stem cells
Konuma, T., Oguro, H., & Iwama, A. (2010) · Development Growth & Differentiation · doi:10.1111/j.1440-169x.2010.01191.x · Cited by 65
“Similarly, mice conditionally depleted of FoxO1, FoxO3a, and FoxO4 in hematopoietic cells showed reduced HSC numbers and activity also associated with increased accumulation of ROS (Tothova et al. 2007).”
BackgroundInfluentialSteroid signaling promotes stem cell maintenance in the Drosophila testis
Li, Y., Ma, Q., Cherry, C., & Matunis, E. L. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.07.016 · Cited by 63
“Stem cells can respond to both local and systemic signals including nutrition and hormones, which convey information about the organism’s environment to the tissues and coordinate responses to physiological change (Drummond-Barbosa, 2008; Drummond-Barbosa and Spradling, 2001; Gancz and Gilboa, 2013; Hsu et al., 2008;…”
BackgroundXia, P., Wang, S., Huang, G., Zhu, P., Li, M., Ye, B., Du, Y., & Fan, Z. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20140169 · Cited by 62
Misra, J., Mohanty, S. T., Madan, S. S., Fernandes, J. A., Ebetino, F. H., Russell, R. G. G., & Bellantuono, I. (2015) · Stem Cells · doi:10.1002/stem.2255 · Cited by 60
Cellular Memory and Hematopoietic Stem Cell Aging
Kamminga, L. M., & de Haan, G. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0345 · Cited by 63
Telomeres, senescence, and hematopoietic stem cells
Zimmermann, S., & Martens, U. M. (2007) · Cell and Tissue Research · doi:10.1007/s00441-007-0469-4 · Cited by 66
“In addition, the dependence of the HSC self-renewal capacity on the inhibition of oxidative stress has been shown in studies with mice deficient for the " ataxia telangiectasia mutated " (Atm) gene resulting in progressive BM failure (Ito et al. 2004).”
BackgroundShen, H., Yu, H., Liang, P. H., Cheng, H., XuFeng, R., Yuan, Y., Zhang, P., Smith, C. A., & Cheng, T. (2012) · Blood · doi:10.1182/blood-2011-08-373621 · Cited by 62
Mas‐Bargues, C., Viña‐Almunia, J., Inglés, M., Sanz‐Ros, J., Gambini, J., Ibáñez-Cabellos, J. S., García‐Giménez, J. L., Viña, J., & Borrás, C. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.002 · Cited by 63
“Ito and colleagues described, both in vitro and in vivo, that activation of p16/pRb gene product pathway in response to elevated ROS led to the failure of hematopoietic stem cells (HSCs) function, and that treatment with antioxidant agents restored the constitutive capacity of HSCs, resulting in the prevention of bone…”
BackgroundKeap1‐Nrf2 system regulates cell fate determination of hematopoietic stem cells
Murakami, S., Shimizu, R., Roméo, P., Yamamoto, M. P., & Motohashi, H. (2014) · Genes to Cells · doi:10.1111/gtc.12126 · Cited by 65
“The ROS accumulation induced by the deletion of Foxo3a, Atm, Tsc1 or Prdm16 leads to HSC exhaustion (Chen et al. 2008; Chuikov et al. 2010; Ito et al. 2004; Miyamoto et al. 2007), indicating that low ROS levels are essential to maintain HSCs quiescent (Jang & Sharkis 2007; Sardina et al. 2012).”
BackgroundWip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways
Chen, Z., Yi, W., Morita, Y., Wang, H., Cong, Y., Liu, J., Xiao, Z., Rudolph, K. L., Cheng, T., & Ju, Z. (2015) · Nature Communications · doi:10.1038/ncomms7808 · Cited by 63
Oxidative stress: A dead end or a laboratory hypothesis?
Azzi, A. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.07.124 · Cited by 64
Metadata
- Authors
- Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., Ikeda, Y., Mak, T. W., & Suda, T.
- Affiliations
- Keio University (JP)
- Kumamoto University (JP)
- University of Toronto (CA)
- Corresponding author
- Hirao, Atsushi
- Suda, Toshio
- ORCID
- Venue
- Nature
- Published
- 2004-10
- Volume
- 431
- Issue
- 7011
- Pages
- 997-1002
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2041897873
- Cited by
- 1,175
- References
- 30
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 38 · 2023: 31 · 2022: 37 · 2021: 51 · 2020: 44 · 2019: 58 · 2018: 47 · 2017: 59 · 2016: 73 · 2015: 71 · 2014: 75 · 2013: 88 · 2012: 77
- FWCI
- 25.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ATM, oxidative stress, hematopoietic stem cells, self-renewal, reactive oxygen species, ataxia telangiectasia, bone marrow failure, p16INK4a, retinoblastoma protein, DNA damage response, antioxidant therapy
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Cell Division, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Retinoblastoma Protein, Protein Serine-Threonine Kinases, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Cell Cycle Proteins, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins
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