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• W2119345707 abstract "Blood homeostasis is maintained by a rare population of quiescent hematopoietic stem cells (HSCs) that self-renew and differentiate to give rise to all lineages of mature blood cells. In contrast to most other blood cells, HSCs are preserved throughout life, and the maintenance of their genomic integrity is therefore paramount to ensure normal blood production and to prevent leukemic transformation. HSCs are also one of the few blood cells that truly age and exhibit severe functional decline in old organisms, resulting in impaired blood homeostasis and increased risk for hematologic malignancies. In this review, we present the strategies used by HSCs to cope with the many genotoxic insults that they commonly encounter. We briefly describe the DNA-damaging insults that can affect HSC function and the mechanisms that are used by HSCs to prevent, survive, and repair DNA lesions. We also discuss an apparent paradox in HSC biology, in which the genome maintenance strategies used by HSCs to protect their function in fact render them vulnerable to the acquisition of damaging genetic aberrations. Blood homeostasis is maintained by a rare population of quiescent hematopoietic stem cells (HSCs) that self-renew and differentiate to give rise to all lineages of mature blood cells. In contrast to most other blood cells, HSCs are preserved throughout life, and the maintenance of their genomic integrity is therefore paramount to ensure normal blood production and to prevent leukemic transformation. HSCs are also one of the few blood cells that truly age and exhibit severe functional decline in old organisms, resulting in impaired blood homeostasis and increased risk for hematologic malignancies. In this review, we present the strategies used by HSCs to cope with the many genotoxic insults that they commonly encounter. We briefly describe the DNA-damaging insults that can affect HSC function and the mechanisms that are used by HSCs to prevent, survive, and repair DNA lesions. We also discuss an apparent paradox in HSC biology, in which the genome maintenance strategies used by HSCs to protect their function in fact render them vulnerable to the acquisition of damaging genetic aberrations. DNA damage is a major driver of genomic instability. If left unrepaired or misrepaired, DNA damage leads to mutations that can result in loss of function or oncogenic transformation [1Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (39909) Google Scholar]. To prevent this scenario, cells can sense DNA damage and activate a series of cellular mechanisms collectively referred to as the DNA damage response (DDR) [2Zhou B.-B.S. Elledge S.J. The DNA damage response: putting checkpoints in perspective.Nature. 2000; 408: 433-439Crossref PubMed Scopus (2592) Google Scholar]. DDR can either promote cell survival through cell cycle arrest and DNA repair or eliminate damaged cells through senescence or apoptosis [3Kuilman T. Michaloglou C. Mooi W.J. Peeper D.S. The essence of senescence.Genes Dev. 2010; 24: 2463-2479Crossref PubMed Scopus (1372) Google Scholar]. DNA is constantly damaged through a variety of intrinsic and extrinsic sources, and it has been estimated that up to 105 DNA lesions occur daily in the genome of a cell [4Hoeijmakers J.H.J. DNA damage, aging, and cancer.N Engl J Med. 2009; 361: 1475-1485Crossref PubMed Scopus (1424) Google Scholar]. Intrinsic sources such as reactive oxygen species (ROS) generated by mitochondrial respiration can cause oxidation of the nucleotide pool and DNA breaks, while spontaneous hydrolysis of DNA can lead to the formation of abasic sites and deamination. In addition, DNA replication or mitosis can give rise to replication errors, telomere attrition, or chromosome missegregation. Extrinsic sources such as irradiation, ultraviolet or genotoxic agents can cause base modifications and single- or double-stranded DNA breaks (SSB/DSB). To repair these lesions, a cell can use a broad array of DNA repair mechanisms, each designed to fix specific types of DNA lesions and to be used in particular phases of the cell cycle [5Branzei D. Foiani M. Regulation of DNA repair throughout the cell cycle.Nat Rev Mol Cell Biol. 2008; 9: 297-308Crossref PubMed Scopus (878) Google Scholar]. DNA lesions including oxidative damage, ultraviolet-induced pyrimidine dimers, or DNA replication errors can be resolved at all stage of the cell cycle by base excision repair, nucleotide excision repair, or mismatch repair, respectively [5Branzei D. Foiani M. Regulation of DNA repair throughout the cell cycle.Nat Rev Mol Cell Biol. 2008; 9: 297-308Crossref PubMed Scopus (878) Google Scholar]. More complex DSBs are repaired by classical or alternative nonhomologous end-joining (NHEJ) throughout the cell cycle and by homologous recombination (HR) during the S/G2 phases in cycling cells [6Shrivastav M. De Haro L.P. Nickoloff J.A. Regulation of DNA double-strand break repair pathway choice.Cell Res. 2008; 18: 134-147Crossref PubMed Scopus (947) Google Scholar]. However, whether NHEJ and HR coordinate or compete for DSB repair during S/G2 phases remains to be clarified. Importantly, the HR pathway is considered error-free because it uses the identical sister chromatid as a template for repair, which is available only in cycling cells. In contrast, NHEJ, especially for the alternative NHEJ pathway, is a more error-prone form of DSB repair as both ends of the broken DNA are directly ligated after processing. This can result in deletions, small insertions, and even translocations if DSBs from different parts of the genome are aberrantly joined [7Lieber M.R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway.Ann Rev Biochem. 2010; 79: 181-211Crossref PubMed Scopus (1812) Google Scholar]. Therefore, the type of DNA lesion and the choice of DNA repair pathway determine the fidelity of repair and the genomic stability of a cell. Upon DNA damage, the DDR coordinates cell cycle progression, repair mechanisms, or the elimination of damaged cells. Key sensors of DNA damages are the Ataxia Telangiectasia Mutated (Atm) and Atm-and-Rad3-related (Atr) kinases. Atm primarily responds to DSBs through its downstream targets Chk2 and various DNA repair proteins [8Sancar A. Lindsey-Boltz L.A. Ünsal-Kaçmaz K. Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.Ann Rev Biochem. 2004; 73: 39-85Crossref PubMed Scopus (2451) Google Scholar]. Atr is mainly activated upon ultraviolet- induced or replication-associated DNA damage through Chk1 phosphorylation, although there is considerable crosstalk between the two pathways [9Jazayeri A. Falck J. Lukas C. et al.ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.Nat Cell Biol. 2006; 8: 37-45Crossref PubMed Scopus (858) Google Scholar]. Downstream of these DDR kinases, the induction of the tumor suppressors p16INK4A and p19ARF further propagates the DDR signal through modulating the retinoblastoma and p53 pathways, respectively [10Sperka T. Wang J. Rudolph K.L. DNA damage checkpoints in stem cells, ageing and cancer.Nat Rev Mol Cell Biol. 2012; 13: 579-590Crossref PubMed Scopus (291) Google Scholar]. In this context, the p53 transcription factor might be the potent DDR mediator, because it is able to orchestrate by itself apoptosis, senescence, and cell cycle progression after DNA damage [11Jackson S.P. Bartek J. The DNA-damage response in human biology and disease.Nature. 2009; 461: 1071-1078Crossref PubMed Scopus (3594) Google Scholar, 12Reinhardt H.C. Schumacher B. The p53 network: cellular and systemic DNA damage responses in aging and cancer.Trends Genet. 2012; 28: 128-136Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. DNA damage is particularly dangerous when it occurs in stem cells. Stem cells are essential for the formation, maintenance, and regeneration of most tissues in adult organisms because of their unique ability to self-renew and to produce all types of differentiated mature cells [13Fuchs E. Tumbar T. Guasch G. Socializing with the neighbors: stem cells and their niche.Cell. 2004; 116: 769-778Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar, 14Mimeault M. Batra S.K. Concise Review: Recent advances on the significance of stem cells in tissue regeneration and cancer therapies.Stem Cells. 2006; 24: 2319-2345Crossref PubMed Scopus (238) Google Scholar]. Preservation of stem cells genomic and functional integrity is therefore essential for proper tissue function. DNA damage can result in apoptosis leading to stem cell attrition and eventually tissue failure or, upon misrepair, in accumulation of mutations eventually contributing to transformation and cancer development [1Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (39909) Google Scholar]. Thus, the response of stem cells to DNA damage must be finely balanced to prevent these deleterious outcomes and to maintain tissue homeostasis. Blood-forming hematopoietic stem cells (HSCs) are one of the best-characterized stem cell population [15Orkin S.H. Zon L.I. Hematopoiesis: An evolving paradigm for stem cell biology.Cell. 2008; 132: 631-644Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar], with a wealth of information currently available on the molecular mechanisms controlling their functional properties including self-renewal activity, cell cycle regulation, and differentiation potential [16Warr M.R. Pietras E.M. Passegué E. Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies.Wiley Interdiscip Rev Syst Biol Med. 2011; 3: 681-701Crossref PubMed Scopus (84) Google Scholar, 17Pietras E.M. Warr M.R. Passegué E. Cell cycle regulation in hematopoietic stem cells.J Cell Biol. 2011; 195: 709-720Crossref PubMed Scopus (278) Google Scholar]. In an adult organism, HSCs reside in the bone marrow (BM) cavity in specialized “niches” that maintain them mainly inactive in the quiescent phase of the cell cycle. However, in response to the need of the organism, HSCs can undergo massive proliferation expansion and produce all types of mature cells needed for blood regeneration. Although HSCs efficiently give rise to all blood cells in young individuals, they often fail with age, resulting in impaired blood production and the development of a broad spectrum of age-related blood diseases [18Rossi D.J. Jamieson C.H.M. Weissman I.L. Stems cells and the pathways to aging and cancer.Cell. 2008; 132: 681-696Abstract Full Text Full Text PDF PubMed Scopus (684) Google Scholar]. This functional decline of old HSCs has, among others, been attributed to the accumulation of DNA damage as based on increased levels of γH2AX foci [19Rossi D.J. Bryder D. Seita J. et al.Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age.Nature. 2007; 447: 725-729Crossref PubMed Scopus (831) Google Scholar, 20Rübe C.E. Fricke A. Widmann T.A. et al.Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging.PLoS ONE. 2011; 6: e17487Crossref PubMed Scopus (217) Google Scholar], a well-known indicator of DSBs. However, it remains controversial whether γH2AX is always a marker of acute or accumulated DNA damage in the absence of exogenous insults. Independently of the age of the stem cell compartment, DNA damage can also occur as a consequence of chemotherapy using DNA damaging agents and lead to the development of either acute myelosuppression and BM failure (BMF) syndromes or therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) [21Godley L.A. Larson R.A. Therapy-related myeloid leukemia.Semin Oncol. 2008; 35: 418-429Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. In addition, many inherited human diseases caused by mutations in DNA repair genes are manifested by hematologic defects, BMF syndromes, and an increased risk for leukemia [22Bakker S.T. de Winter J.P. Riele H.T. Learning from a paradox: recent insights into Fanconi anaemia through studying mouse models.Dis Model Mech. 2013; 6: 40-47Crossref PubMed Scopus (43) Google Scholar, 23Blanpain C. Mohrin M. Sotiropoulou P.A. Passegué E. DNA-damage response in tissue-specific and cancer stem cells.Cell Stem Cell. 2011; 8: 16-29Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar]. Therefore, determining how HSCs respond to DNA damage and maintain their genomic integrity is crucial for understanding the fundamental mechanisms of aging and leukemic transformation in the blood system. Here, we review how DNA damage is generated in HSCs and how HSCs cope with insults to their genome. We mainly focus on recent insights gained from mouse studies on HSC genome maintenance strategies and only touch upon some of the main DNA repair mechanisms acting in HSCs and how their defects contribute to congenital and acquired blood diseases in humans, because these aspects have been covered in detail previously [23Blanpain C. Mohrin M. Sotiropoulou P.A. Passegué E. DNA-damage response in tissue-specific and cancer stem cells.Cell Stem Cell. 2011; 8: 16-29Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 24Park Y. Gerson S.L. DNA repair defects in stem cell function and aging.Stem Cells. 2008; 1: 495-508Google Scholar, 25Kottemann M.C. Smogorzewska A. Fanconi anaemia and the repair of Watson and Crick DNA crosslinks.Nature. 2013; 493: 356-363Crossref PubMed Scopus (424) Google Scholar]. We describe how the unique molecular wiring of HSCs both safeguards them against the occurrence of DNA damage and ensures their survival but, paradoxically, also makes them susceptible to acquiring mutations and genomic instability. Given the lifelong potential for genomic lesions to hamper HSC function, one solution selected by evolution has been to develop an array of protective mechanisms that minimize their occurrence in the first place. DNA lesions can originate from replicative, oxidative, or environmental stress. These genotoxic stresses are interconnected, and it is logical that the strategies to minimize them are often overlapping. Figure 1 summarizes the main protective strategies used by HSCs to ensure their function and minimize genomic instability. The main protective strategy against replication stress is to restrict HSCs to a quiescent or dormant (G0) cell cycle state that prevents DNA damage associated with DNA replication and mitosis [17Pietras E.M. Warr M.R. Passegué E. Cell cycle regulation in hematopoietic stem cells.J Cell Biol. 2011; 195: 709-720Crossref PubMed Scopus (278) Google Scholar, 26Wilson A. Laurenti E. Oser G. et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (1325) Google Scholar, 27Orford K.W. Scadden D.T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation.Nat Rev Genet. 2008; 9: 115-128Crossref PubMed Scopus (648) Google Scholar]. Quiescence is unique to adult HSCs, because fetal or postnatal HSCs are predominately found in an active cell cycle state [15Orkin S.H. Zon L.I. Hematopoiesis: An evolving paradigm for stem cell biology.Cell. 2008; 132: 631-644Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar, 17Pietras E.M. Warr M.R. Passegué E. Cell cycle regulation in hematopoietic stem cells.J Cell Biol. 2011; 195: 709-720Crossref PubMed Scopus (278) Google Scholar]. Within the adult pool, HSCs with the largest self-renewal capacity also divide the least—once every 145 days approximately five times during the lifespan of a mouse [26Wilson A. Laurenti E. Oser G. et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (1325) Google Scholar]. However, most mouse HSCs divide once every 30 days to ensure homeostatic blood production [17Pietras E.M. Warr M.R. Passegué E. Cell cycle regulation in hematopoietic stem cells.J Cell Biol. 2011; 195: 709-720Crossref PubMed Scopus (278) Google Scholar]. In parallel, simulation studies in humans propose that HSCs divide every 40 weeks, indicating that the numbers of HSC replications per lifetime are comparable between mouse and human [28Catlin S.N. Busque L. Gale R.E. Guttorp P. Abkowitz J.L. The replication rate of human hematopoietic stem cells in vivo.Blood. 2011; 117: 4460-4466Crossref PubMed Scopus (137) Google Scholar]. Actively cycling HSCs exhibit reduced self-renewal capacity, and many studies have correlated the loss of quiescence and increased proliferation activity to functional decline of both murine and human HSCs [27Orford K.W. Scadden D.T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation.Nat Rev Genet. 2008; 9: 115-128Crossref PubMed Scopus (648) Google Scholar, 29Yahata T. Takanashi T. Muguruma Y. et al.Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells.Blood. 2011; 118: 2941-2950Crossref PubMed Scopus (216) Google Scholar]. The importance of quiescence for HSC function is further demonstrated by the unique molecular wiring of their cell cycle machinery and the predominance of p53 and the cyclin D1/p57 axis in enforcing quiescence [17Pietras E.M. Warr M.R. Passegué E. Cell cycle regulation in hematopoietic stem cells.J Cell Biol. 2011; 195: 709-720Crossref PubMed Scopus (278) Google Scholar, 26Wilson A. Laurenti E. Oser G. et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (1325) Google Scholar]. The switch between quiescence and cell cycle progression appears to be regulated in a more stringent and nonredundant fashion in HSCs compared with other cell types, because disruption of cell cycle proteins often results in HSC-specific phenotypes. One example is cyclin A2, which is essential for HSC proliferation but dispensable for fibroblast proliferation because of redundancy with cyclin E [30Kalaszczynska I. Geng Y. Iino T. et al.Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells.Cell. 2009; 138: 352-365Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar]. Another example is p57 inactivation, which has no effect on hematopoietic progenitors but leads to the loss of HSC quiescence, a decrease in HSC number and function, and an increase in p53-mediated apoptosis [31Matsumoto A. Takeishi S. Kanie T. et al.p57 is required for quiescence and maintenance of adult hematopoietic stem cells.Cell Stem Cell. 2011; 9: 262-271Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 32Zou P. Yoshihara H. Hosokawa K. et al.p57Kip2 and p27Kip1 cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70.Cell Stem Cell. 2011; 9: 247-261Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]. Overall, quiescence is essential for the maintenance of HSCs in adult organisms, and it acts as the main protective mechanism against replication-associated DNA damage. Normally, HSCs have low ROS levels, which serve as important signaling molecules for differentiation [33Owusu-Ansah E. Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation.Nature. 2009; 461: 537-541Crossref PubMed Scopus (547) Google Scholar], whereas myeloid progenitors have 100-fold higher ROS levels [34Tothova Z. Kollipara R. Huntly B.J. et al.FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar]. Excessive ROS are detrimental to HSC function, and one of the first studies demonstrating a direct link between high ROS and loss of HSC function was actually conducted in mice deficient for the DDR gene Atm. 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 p16INK4A/p19ARF expression [35Ito K. Hirao A. Arai F. et al.Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells.Nature. 2004; 431: 997-1002Crossref PubMed Scopus (941) Google Scholar, 36Ito K. Hirao A. Arai F. et al.Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.Nat Med. 2006; 16: 129Crossref Scopus (3) Google Scholar]. Loss of HSC function is caused by elevated ROS and consequent activation of the p38 MAPK pathway, as reducing ROS through treatment with an antioxidant, N-acetylcysteine or p38 inhibition rescue Atm-deficient HSC function [35Ito K. Hirao A. Arai F. et al.Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells.Nature. 2004; 431: 997-1002Crossref PubMed Scopus (941) Google Scholar, 36Ito K. Hirao A. Arai F. et al.Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.Nat Med. 2006; 16: 129Crossref Scopus (3) Google Scholar]. Furthermore, lymphoma development in Atm-deficient mice could be delayed by antioxidant treatment, demonstrating that excessive ROS directly lead to genomic instability and transformation in this mouse model [37Schubert R. Erker L. Barlow C. et al.Cancer chemoprevention by the antioxidant Tempol in Atm-deficient mice.Hum Mol Genet. 2004; 13: 1793-1802Crossref PubMed Scopus (126) Google Scholar]. The importance of maintaining low ROS appears as a general requirement for HSC maintenance. For example, HSCs deficient in all three FoxO transcription factors (FoxO1, FoxO3, and FoxO4) or FoxO3a alone lose quiescence, have increased apoptosis and reduced self-renewal capacity [34Tothova Z. Kollipara R. Huntly B.J. et al.FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar, 38Miyamoto K. Araki K.Y. Naka K. et al.Foxo3a is essential for maintenance of the hematopoietic stem cell pool.Cell Stem Cell. 2007; 1: 101-112Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar]. FoxO transcription factors control ROS by regulating genes involved in ROS detoxification and cell cycle progression [34Tothova Z. Kollipara R. Huntly B.J. et al.FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar, 39Tothova Z. Gilliland D.G. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system.Cell Stem Cell. 2007; 1: 140-152Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. The loss of HSC function in the FoxO1/3/4-deficient mouse model is again a consequence of high ROS levels, as reducing ROS through antioxidant treatment restored HSC quiescence and function [34Tothova Z. Kollipara R. Huntly B.J. et al.FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar]. Functional studies in both humans and mice cells have also shown that chemical induction of oxidative stress or serial transplantation result in elevated ROS, increased HSC proliferation, and HSC functional exhaustion, which can be inhibited by antioxidant treatment or p38 inhibition [29Yahata T. Takanashi T. Muguruma Y. et al.Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells.Blood. 2011; 118: 2941-2950Crossref PubMed Scopus (216) Google Scholar, 36Ito K. Hirao A. Arai F. et al.Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.Nat Med. 2006; 16: 129Crossref Scopus (3) Google Scholar]. In these contexts, high ROS levels are also directly correlated to increased DNA damage, as assayed by yH2AX foci and expression of proteins involved in the DDR pathway [29Yahata T. Takanashi T. Muguruma Y. et al.Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells.Blood. 2011; 118: 2941-2950Crossref PubMed Scopus (216) Google Scholar]. Taken together, these results demonstrate that oxidative stress can cause DNA damage and contribute to the loss of quiescence and functional impairment in HSCs. It is tempting to speculate that ROS-induced DNA damage is the main driver of reduced HSC function in Atm- or FoxO-deficient mouse models; however, its involvement has not been formally demonstrated. Recent studies suggest an additional layer of complexity because Atm also acts as a redox sensor independently of its role in the canonical DDR pathway, and it activates cell-cycle checkpoints in response to oxidative stress [40Guo Z. Kozlov S. Lavin M.F. Person M.D. Paull T.T. ATM activation by oxidative stress.Science. 2010; 330: 517-521Crossref PubMed Scopus (771) Google Scholar] and deregulated mitochondrial homeostasis [41Valentin-Vega Y.A. MacLean K.H. Tait-Mulder J. et al.Mitochondrial dysfunction in ataxia-telangiectasia.Blood. 2012; 119: 1490-1500Crossref PubMed Scopus (277) Google Scholar]. Therefore, low or absent Atm could impair HSC function by both failing to induce a correct checkpoint response after high ROS levels and impairing the repair of ROS-mediated DNA damage. Interestingly, the deletion of all three FoxO transcription factors or FoxO3 alone leads to decreased expression of Atm [34Tothova Z. Kollipara R. Huntly B.J. et al.FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar, 42Yalcin S. Zhang X. Luciano J.P. et al.Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells.J Biol Chem. 2008; 283: 25692-25705Crossref PubMed Scopus (200) Google Scholar], thus linking at least two of the important regulatory pathways controlling oxidative stress. In turn, Atm could regulate the response to oxidative stress and low levels of DNA damage in HSCs in part by phosphorylating Bid, a BH3-only proapoptotic BCL2 family member [43Maryanovich M. Oberkovitz G. Niv H. et al.The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells.Nat Cell Biol. 2012; 14: 535-541Crossref PubMed Scopus (114) Google Scholar]. In the absence of Atm, HSCs have increased apoptosis following irradiation, loss of quiescence, decreased self-renewal, and increased ROS because of Bid accumulation in mitochondria [43Maryanovich M. Oberkovitz G. Niv H. et al.The ATM-BID pathway regulates quiescence and survival of haematopoietic stem cells.Nat Cell Biol. 2012; 14: 535-541Crossref PubMed Scopus (114) Google Scholar]. These studies illustrate the central role of Atm in dampening the mutagenic consequences of oxidative stress in HSCs through regulation of DNA repair, cell cycle, and apoptosis. Collectively, they show that keeping ROS levels in check and minimizing oxidative stress is critical for HSC genomic stability. Checkpoint activation is a potent strategy to minimize genomic instability [2Zhou B.-B.S. Elledge S.J. The DNA damage response: putting checkpoints in perspective.Nature. 2000; 408: 433-439Crossref PubMed Scopus (2592) Google Scholar]. Mice with deletion of the Polycomb repressor Bmi1 display reduced HSC self-renewal capacity, high ROS, and shortened life span [44Liu J. Cao L. Chen J. et al.Bmi1 regulates mitochondrial function and the DNA damage response pathway.Nature. 2009; 459: 387-392Crossref PubMed Scopus (374) Google Scholar]. In addition, disruption of Bmi1 leads to activation of the DDR pathway demonstrated by Chk2 expression and increased expression of p16nk4a and p19Arf [44Liu J. Cao L. Chen J. et al.Bmi1 regulates mitochondrial function and the DNA damage response pathway.Nature. 2009; 459: 387-392Crossref PubMed Scopus (374) Google Scholar]. Interestingly, lowering ROS or inactivation of the DDR through Chk2 disruption increases the lifespan of Bmi1-deficient mice but does not restore HSC self-renewal [44Liu J. Cao L. Chen J. et al.Bmi1 regulates mitochondrial function and the DNA damage response pathway.Nature. 2009; 459: 387-392Crossref PubMed Scopus (374) Google Scholar]. This finding demonstrates that HSC function is hampered in the absence of Bmi-1, independently of high ROS. This is likely the result of continued activation of p16Ink4a and p19Arf because their expression levels are not normalized after antioxidant treatment or Chk2 disruption [44Liu J. Cao L. Chen J. et al.Bmi1 regulates mitochondrial function and the DNA damage response pathway.Nature. 2009; 459: 387-392Crossref PubMed Scopus (374) Google Scholar]. HSCs lacking Pten, a phosphatase that inactivates PI3-K signaling and negatively regulates the mTOR pathway, also display increased cell cycle activity and impaired self-renewal capacity, with Pten-deficient mice succumbing to leukemia [45Yilmaz Ö.H. Valdez R. Theisen B.K. et al.Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.Nature. 2006; 441: 475-482Crossref PubMed Scopus (1103) Google Scholar, 46Zhang J. Grindley J.C. Yin T. et al.PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention.Nature. 2006; 441: 518-522Crossref PubMed Scopus (669) Goo" @default.
• W2119345707 created "2016-06-24" @default.
• W2119345707 creator A5016128169 @default.
• W2119345707 creator A5062527795 @default.
• W2119345707 date "2013-11-01" @default.
• W2119345707 modified "2023-10-14" @default.
• W2119345707 title "Resilient and resourceful: Genome maintenance strategies in hematopoietic stem cells" @default.
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