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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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“Perspectives Ces résultats mettent en perspective d’autres observations similaires rapportées récemment au cours de l’étude de modèles murins d’inactivation du facteur PTEN [5, 6], situé en amont de FoxO dans la voie PI3K/AKT, et du facteur de transcription ATM (ataxia telangiectasia mutated) [7].”
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“leading to loss of quiescence ( Ito et al., 2004, 2006 ).”
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“This response may be a consequence of the role of ATM in controlling ROS generation; when ATM is inhibited ROS accumulation could trigger a G1 checkpoint.(10) However, a ROS inhibitor did not relieve the G1 block and this is a question that requires further investigation.”
BackgroundDNA Repair in Normal Stem Cells
Momčilović, O., & Schatten, G. P. (2012) · Springer eBooks · doi:10.1007/978-94-007-4590-2_4 · Cited by 2
“sive bone marrow failure in adult mice due to increased ROS production [149, 150].”
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“by accumulation of DNA damage in stem cells (Rübe et al. 2011; Ito et al. 2004; Rossi et al. 2007).”
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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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