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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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“Atm HSCs failed to engraft longterm in competitive transplantation assays [15].”
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“Although ROS have been shown to suppress the proliferation and differentiation capacity of hematopoietic progenitors and induce apoptosis of mature cells of the hematopoietic lineage (32,33), the sharp decrease in leukocyte counts in the peripheral blood after abdominal irradiation, a sign of hematopoietic suppression…”
Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs
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“The paradigm is in part based on the finding that mice lacking a distinct set of DNA damage repair proteins display reduced function ofHSCs, including an impaired repopulating potential and an overall depletion of the HSC pool (Ito et al., 2004; Navarro et al., 2006;Nijnik et al., 2007;Parmaret al., 2010;Prasher et al…”
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“These HSC defects are associated with high levels of ROS, since treatment with the antioxidant NAC significantly improves HSC reconstitution capacity in Atm mice [51].”
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“It has been reported that hematopoietic stem cells [69] and central nervous system stem cells [70] exhibit lower levels of ROS compared to their more mature progeny.”
Tissue specificity of DNA damage response and tumorigenesis
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Oxidative stress regulates progenitor behavior and cortical neurogenesis
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“Cellular ROS levels have been demonstrated to regulate the property and behavior of different cell types, especially stem cells (Bigarella et al., 2014; Ito et al., 2004; Liu et al., 2009; Madhavan et al., 2006; Yoneyama et al., 2010).”
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“Similar to the observations in FA patients,22 we found that Trp53 is crucially involved in the exhaustion of HSPCs in Ercc1-/*292mice and that deletion of Trp53 restored the colony-forming capacity and the LSK content of Ercc1-/*292 HSPCs.”
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“It was shown that the self-renewal capacity of HSCs depended on the ATM-mediated inhibition of oxidative stress associated with elevated ROS, while the addition of anti-oxidative agents restored the reconstitution capacity of ATM−/− HSCs (Ito et al., 2004).”
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“…regenerative failures are observed in some form or another in each of these models, and recent reports indicate that mutation of many of these same genome-maintenance regulators leads to decreased stem cell number and potential with age (Ito et al, 2004; Nijnik et al, 2007; Rossi et al, 2007).”
ResultWambi, C. O., Sanzari, J. K., Sayers, C. M., Nuth, M., Zhou, Z., Davis, J. G., Finnberg, N. K., Lewis-Wambi, J. S., Ware, J. H., El‐Deiry, W. S., et al. (2009) · Radiation Research · doi:10.1667/rr1708.1 · Cited by 51
“Treatment of adult mice lacking the ataxia telangiectasia mutated gene (Atm2/2) with NAC or catalase not only prevents elevation in ROS but also results in partial rescue of bone marrow failure associated with increased chronic p38 MAPK-induced ROS (51, 52).”
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Protection of hematopoietic stem cells from stress-induced exhaustion and aging
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“Increased ROS in HSCs promotes increased proliferation, differentiation, and loss of HSC function and exhaustion [25,30,31].”
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“However, the antioxidant capacity of oxidized ATM plays a key role in the proliferation of haematopoietic stem cells.(12) The reason for this discrepancy may indicate the cellular specificity of the antioxidant function of oxidized ATM in regulating cell proliferation.”
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“Atm is preferentially expressed in active cycling cells and regulates self-renewal, but not proliferation or differentiation [32, 33].”
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“This is of particular relevance since recent reports have highlighted the importance of these pathways in the selfrenewal and control of life span of HSC [40,41].”
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“Regulation of ROS through FOXO proteins and ATM appear to be required for stem cell quiescence and repopulating ability [48,49].”
BackgroundExploring metabolic pathways that contribute to the stem cell phenotype
Vacanti, N. M., & Metallo, C. M. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.08.007 · Cited by 51
A functional single nucleotide polymorphism in promoter of ATM is associated with longevity
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“Mice with the ATM gene knocked out have progressive bone marrow failure resulting from a defect in hematopoietic stem cells function due to elevated ROS (Ito et al., 2004).”
BackgroundInfluentialHematopoiesis and stem cell renewal in long-term bone marrow cultures containing catalase
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Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison
Romo-González, M., Ijurko, C., & Hernández‐Hernández, Á. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.889875 · Cited by 53
“As reviewed elsewhere (12), gene targeting experiments have revealed certain key genes in maintaining low ROS levels in HSC, such as FoxO transcription factors (17), tuberous sclerosis complex 1 (Tsc1) (18), ataxia–telangiectasia mutated gene (Atm) (19), and polycomb group (PcG) Bmi1 (20).”
BackgroundOxidative stress and the multifaceted roles of ATM in maintaining cellular redox homeostasis
Lee, J. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103269 · Cited by 54
“…consistently reveal significantly higher intra-cellular ROS levels, especially H2O2, in various ATM-deficient cell types, including hematopoietic stem cells [29], cerebellar neurons, and specific brain regions like the cerebellum, basal ganglia, hippocampal CA1, and substantia nigra [30].”
BackgroundRoles of IDH1/2 and TET2 mutations in myeloid disorders
Inoue, S., Lemonnier, F., & Mak, T. W. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-1973-7 · Cited by 52
Self-citationATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy
Antonelli, M., Strappazzon, F., Arisi, I., Brandi, R., D’Onofrio, M., Sambucci, M., Manic, G., Vitale, I., Barilà, D., & Stagni, V. (2017) · Oncotarget · doi:10.18632/oncotarget.15537 · Cited by 50
“In this study, the treatment of Atm-/- mice with antioxidant N-acetylcystine (NAC) restored the HSC pool, confirming the critical role of ROS regulation by ATM for stemness [40].”
BackgroundMethodPoly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency
Lee, J., Ryu, S. W., Ender, N. A., & Paull, T. T. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.019 · Cited by 52
p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses
Wang, Y., Sharpless, N. E., & Chang, S. S. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69574 · Cited by 49
“These results suggest that one mechanism underlying p16INK4a-mediated cellular impairments in hematopoietic stem cells might be due to p16INK4a upregulation by chronic DNA damage resulting from progressive telomere dysfunction that limits stem cell self-renewal capacity (40).”
Biechonski, S., Yassin, M., & Milyavsky, M. (2017) · Carcinogenesis · doi:10.1093/carcin/bgx002 · Cited by 54
“ATM, Ataxia telangiectasia Progressive BM failure (27) Mild immunodeficiency”
BackgroundDNA Damage Responses and Oxidative Stress in Dyskeratosis Congenita
Pereboeva, L., Westin, E. R., Patel, T., Flaniken, I. Z., Lamb, L. S., Klingelhutz, A. J., & Goldman, F. D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076473 · Cited by 48
“NAC can also partially correct stem cell defects in other premature aging models such ATM-deficiency or in mice lacking transcription factors FoxOs 1, 3, and 5 [37] [38].”
BackgroundThomas, P. D., & Kahn, M. (2016) · Cell Biology and Toxicology · doi:10.1007/s10565-016-9318-0 · Cited by 48
“Lower ROS levels and a reducing redox microenvironment have been shown to be crucial for SSC maintenance and function (Ito et al. 2004).”
Inflammation, a significant player of Ataxia–Telangiectasia pathogenesis?
Zaki‐Dizaji, M., Akrami, S. M., Azizi, G., Abolhassani, H., & Aghamohammadi, A. (2018) · Inflammation Research · doi:10.1007/s00011-018-1142-y · Cited by 49
The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability
Shiloh, Y. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102950 · Cited by 48
Critical Roles for Polymerase ζ in Cellular Tolerance to Nitric Oxide–Induced DNA Damage
Wu, X., Takenaka, K., Sonoda, E., Hochegger, H., Kawanishi, S., Kawamoto, T., Takeda, S., & Yamazoe, M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2884 · Cited by 47
“Likewise, atm cells, which are defective of double-strand break–induced damage checkpoint (36, 37) and susceptible to oxidative stress (38), did not display hypersensitivity to NO treatment.”
BackgroundThe hallmarks of aging in Ataxia-Telangiectasia
Aguado, J., Gómez‐Inclán, C., Leeson, H. C., Lavin, M. F., Shiloh, Y., & Wolvetang, E. J. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101653 · Cited by 47
New Insights into Mitochondria in Health and Diseases
Li, Y., Zhang, H., Yu, C., Dong, X., Yang, F., Wang, M., Wen, Z., Su, M., Li, B., & Yang, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25189975 · Cited by 48
“…a continuous decrease Excessive exposure to ROS leads to oxidative stress, resulting in protein oxidation and mutations in mitochondrial DNA [34– 36]. in ATP leads to abnormal energy consumption, impeding the process of autophagy in the mitochondria, decreasing the production Abnormal…”
BackgroundImplication of oxidative stress as a cause of autoimmune hemolytic anemia in NZB mice
Iuchi, Y., Kibe, N., Tsunoda, S., Suzuki, S., Mikami, T., Okada, F., Uchida, K., & Fujii, J. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.01.012 · Cited by 46
Angiopoietins contribute to lung development by regulating pulmonary vascular network formation
Hato, T., Kimura, Y., Morisada, T., Koh, G. Y., Miyata, K., Tabata, M., Kadomatsu, T., Endo, M., Urano, T., Arai, F., et al. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.02.030 · Cited by 46
Self-citationInactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4
Castex, J., Willmann, D., Kanouni, T., Arrigoni, L., Li, Y., Friedrich, M. E., Schleicher, M., Wöhrle, S., Pearson, M. A., Kraut, N., et al. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.48 · Cited by 46
“Stem cells are particular sensitive to increased oxidants 11 suggesting a link between high ROS levels and a decline in stem cell number during aging.(12,13) The ability of cells to antagonize oxidative damage is determined by a controlled balance between the emergence of ROS and the capacity to generate antioxidants.”
BackgroundHira, V. V. V., Noorden, C. J. F. V., Carraway, H. E., Maciejewski, J. P., & Molenaar, R. J. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.03.010 · Cited by 48
Lavorgna, M., Orlo, E., Nugnes, R., Piscitelli, C., Russo, C., & Isidori, M. (2019) · Plant Foods for Human Nutrition · doi:10.1007/s11130-019-00722-0 · Cited by 46
Ferro, F., Spelat, R., Shaw, G., Duffy, N., Islam, M. N., O’Shea, P. M., O’Toole, D. P., Howard, L., & Murphy, M. J. (2019) · Stem Cells · doi:10.1002/stem.2998 · Cited by 48
The response to DNA damage during differentiation: Pathways and consequences
Fortini, P., Ferretti, C., & Dogliotti, E. (2013) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2013.03.004 · Cited by 45
Mechanisms involved in hematopoietic stem cell aging
Fujino, T., Asada, S., Goyama, S., & Kitamura, T. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04356-5 · Cited by 49
“In addition, the ataxia telangiectasia mutated (ATM) protein can protect HSCs from oxidative stress, although the underlying mechanisms remain unclear [74].”
BackgroundMetabolic plasticity and hematopoietic stem cell biology
Hsu, P., & Qu, C. (2013) · Current Opinion in Hematology · doi:10.1097/moh.0b013e328360ab4d · Cited by 47
“telangiectasia mutated) leads to progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated ROS, demonstrating that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress [14].”
Epigenetic Regulation of Hematopoietic Stem Cell Self-Renewal by Polycomb Group Genes
Iwama, A., Oguro, H., Negishi, M., Kato, Y., & Nakauchi, H. (2005) · International Journal of Hematology · doi:10.1532/ijh97.05011 · Cited by 46
“The important role of the Ink4a locus in HSC self-renewal is supported by a recent finding that activation of the p16 INK4A ‐retinoblastoma gene product pathway in response to elevated levels of reactive oxygen species in ATM-deficient mice leads to impaired HSC selfrenewal [ 37 ].”
BackgroundLilly, A. J., Johnson, W. E. B., & Bunce, C. M. (2011) · Stem Cells International · doi:10.4061/2011/274564 · Cited by 46
“Other than causing cellular damage, data suggests that ROS activates the P38 MAPK pathway, which decreases adhesion molecule expression and enhances cell cycle progression [112, 114, 115].”
BackgroundNADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease
Weyemi, U., Redon, C. E., Aziz, T., Choudhuri, R., Maeda, D., Parekh, P. R., Bonner, M. Y., Arbiser, J. L., & Bonner, W. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1418139112 · Cited by 47
“ATM-deficient mice fed with antioxidants lived longer, exhibited a reduced incidence of lymphoma and showed mitigated loss of hematopoietic stem cells compared with controls (15, 16).”
BackgroundStem Cells Seen Through the FOXO Lens: An Evolving Paradigm
Liang, R. H.-S., & Ghaffari, S. (2018) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2017.11.006 · Cited by 45
Ludikhuize, M. C., & Colman, M. J. R. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8126 · Cited by 45
“Moreover, a mild increase in ROS levels is associated with loss of HSC quiescence, elevated hematopoietic progenitor production, and compromised long-term in vivo repopulation capacity of HSCs (64, 71, 87, 95, 110, 181, 182).”
Mitochondrial Contributions to Hematopoietic Stem Cell Aging
Morganti, C., & Ito, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011117 · Cited by 50
“Murine models of ATM loss show defects in DNA damage repair associated with mitochondrial dysfunction [83] and loss of hematopoietic stem cell (HSC) potential [23].”
BackgroundSelf-citationGu, B.-W., Fan, J., Bessler, M., & Mason, P. J. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00674.x · Cited by 45
“Whether the increase in ROS that we observe accumulating in mutant cells is a consequence of the DNA damage Stem cell aging in Dkc1 mutant mice, B.-W. Gu et al. ª 2011 The Authors Aging Cell ª 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 344 response mediated by ATM ⁄ p53 ⁄ p21 (Macip…”
BackgroundInfluentialGatzka, M., Tasdogan, A., Hainzl, A., Allies, G., Maity, P., Wilms, C., Wlaschek, M., & Scharffetter‐Kochanek, K. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2014.231 · Cited by 48
The mitochondrial metabolic checkpoint and aging of hematopoietic stem cells
Mohrin, M., & Chen, D. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000244 · Cited by 46
DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation
Uyanik, B., Grigorash, B. B., Goloudina, A. R., & Demidov, O. N. (2017) · Cell Death Discovery · doi:10.1038/cddiscovery.2017.18 · Cited by 47
Henry, E., Souissi, I., Deynoux, M., Lefèvre, A., Barroca, V., Campalans, A., Ménard, V., Calvo, J., Pflumio, F., & Arcangeli, M.-L. (2019) · Haematologica · doi:10.3324/haematol.2019.226936 · Cited by 43
Yoshida, K., Kirito, K., Hu, Y., Ozawa, K., Kaushansky, K., & Komatsu, N. (2008) · International Journal of Hematology · doi:10.1007/s12185-008-0091-6 · Cited by 44
“impairs hematopoiesis as the ROS scavenger NAC improved ROS-induced hematopoietic defects [ 33 ], an effect dependent on the p38 MAPK pathway [34].”
BackgroundLife and death in hematopoietic stem cells
Oguro, H., & Iwama, A. (2007) · Current Opinion in Immunology · doi:10.1016/j.coi.2007.05.001 · Cited by 46
Urao, N., McKinney, R. D., Fukai, T., & Ushio‐Fukai, M. (2012) · Stem Cells · doi:10.1002/stem.1048 · Cited by 43
Targeting stem cell niches and trafficking for cardiovascular therapy
Kränkel, N., Spinetti, G., Amadesi, S., & Madeddu, P. R. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.10.002 · Cited by 43
“In genetically-modified animals unable to modulate ROS production, administration of the anti-oxidant agent N-acetyl-L-cysteine restored the reconstitutive capacity of hematopoietic SC, thereby preventing BM failure (Ito et al., 2004; Tothova et al., 2007).”
BackgroundShiozawa, Y., & Taichman, R. S. (2012) · Experimental Hematology · doi:10.1016/j.exphem.2012.05.004 · Cited by 44
“It has been also demonstrated that oxidative stress reverses HSC dormancy [100,101].”
BackgroundRedox-regulated fate of neural stem progenitor cells
Prozorovski, T., Schneider, R., Berndt, C., Hartung, H., & Aktaş, O. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2015.01.022 · Cited by 45
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Denu, R. A., & Hematti, P. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.042 · Cited by 43
ATM at the crossroads of reactive oxygen species and autophagy
Xie, X., Zhang, Y., Wang, Z., Wang, S., Jiang, X.-Y., Cui, H., Zhou, T., He, Z., Feng, H., Guo, Q., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.63963 · Cited by 44
“ATM also plays a role in regulating oxidative stress in nerve cells [52, 53].”
Background
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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