Blood Cells, Molecules and Diseases 52 (2014) 147–151

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Review

DNA damage response in adult stem cells Alessandra Insinga a, Angelo Cicalese a, Pier Giuseppe Pelicci a,b,⁎ a b

Department of Experimental Oncology, European Institute of Oncology, IEO, 20141 Milan, Italy Dipartimento di Medicina, Chirurgia e Odontoiatria, Università degli Studi di Milano, 20122 Milan, Italy

a r t i c l e

i n f o

a b s t r a c t

Article history: Submitted 8 November 2013 Available online 28 January 2014

This review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span of stem cells suggests that they may respond differently to DNA damage than their downstream progeny and, indeed, studies have begun to elucidate the unique stem cell response mechanisms to DNA damage. Because the DNA damage responses in stem cells and progenitor cells are distinctly different, stem and progenitor cells should be considered as two different entities from this point of view. Hematopoietic and mammary stem cells display a unique DNA-damage response, which involves active inhibition of apoptosis, entry into the cell-cycle, symmetric division, partial DNA repair and maintenance of self-renewal. Each of these biological events depends on the up-regulation of the cell-cycle inhibitor p21. Moreover, inhibition of apoptosis and symmetric stem cell division are the consequence of the down-regulation of the tumor suppressor p53, as a direct result of p21 up-regulation. A deeper understanding of these processes is required before these findings can be translated into human anti-aging and anti-cancer therapies. One needs to clarify and dissect the pathways that control p21 regulation in normal and cancer stem cells and define (a) how p21 blocks p53 functions in stem cells and (b) how p21 promotes DNA repair in stem cells. Is this effect dependent on p21s ability to inhibit p53? Such molecular knowledge may pave the way to methods for maintaining short-term tissue reconstitution while retaining long-term cellular and genomic integrity. © 2013 Published by Elsevier Inc.

(Communicated by Grover C. Bagby, M.D., 5 December 2013) Keywords: Stem cells DNA damage Self-renewal Cancer aging

Contents Introduction . . . . . . . . DNA damage processing in SCs Impact on aging and cancer . Conflict of Interest. . . . . . Acknowledgments . . . . . References . . . . . . . . .

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Introduction DNA integrity is fundamental for cell survival and maintenance of tissue homeostasis. Any kind of DNA damage (DD) is rapidly sensed by the cell and activates evolutionary conserved and well-characterized signaling pathways, collectively known as the DNA damage response (DDR) [1,2]. This response has two important outcomes: it prevents cell-cycle progression and coordinates efforts devoted at repairing DNA. Briefly, single-stranded DNA and double-strand breaks are detected by specialized sensor complexes which then recruit and activate

⁎ Corresponding author at: Department of Experimental Oncology, European Institute of Oncology, IEO, 20141 Milan, Italy. E-mail address: [email protected] (P.G. Pelicci). 1079-9796/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.bcmd.2013.12.005

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apical protein kinases, respectively ATR (ataxia telangiectasia and Rad3 related) or ATM (ataxia telangiectasia mutated), to the site of damage [1,3,4]. The recruitment of these signal transducers to the DNA lesion causes phosphorylation of the histone H2A histone-variant (H2AX), which is essential in the nucleation of the DDR [5]. At sites of DD, ATM and ATR activities are amplified by DD mediators [2,6–10]. When local ATM or ATR activity exceeds a certain threshold, DDR factors that function far from the site of damage are engaged [11]. ATM phosphorylates and activates the checkpoint kinase CHK2, while CHK1 is principally phosphorylated by ATR (but also by ATM). These downstream kinases diffuse throughout the nucleus and spread the DDR signal by phosphorylating their substrates [12,13]. Ultimately, activation of the DDR signaling cascade converges upon the key decision-making factor p53 [2,14]. p53 is phosphorylated and stabilized; it accumulates in the nucleus and activates its target genes. Depending on the target genes that are

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activated, p53 regulates different cellular outcomes: cell-cycle arrest (through induction of the cyclin-dependent kinase inhibitor p21), or apoptosis (through transcriptional activation of the bcl2 family members bax, noxa, and puma). The DDR signaling cascade has been extensively studied and characterized in cell lines and primary cells like murine embryo fibroblasts (MEFs). In contrast, little is known about the DDR in vivo. Interestingly, in vivo evidence of DD and DDR cascade activation comes from several recent reports on human and mouse pre-malignant lesions of different origins, namely lung, prostate, bladder, melanocytic nevi and lymphoid derivation [15–21]. DD in these cells accumulates due to oncogene-driven cell-division cycles and is associated with DNA replication. These benign lesions consist of senescent cells that express activated oncogenes, show H2AX phosphorylation, display active forms of ATM/ATR, Chk1 and, most importantly, show p53 stabilization. Indeed, genetically, oncogene induced senescence is dependent on p53, as elegantly shown in the prostate and confirmed in the lung and pancreas and in lymphoid cells. Notably, active DDR markers and a senescence status were detected in bulk pre-cancerous lesions, mostly consisting of progenitor cells, while no information was provided on stem cells (SCs). Equally, the mechanism through which normal SCs respond to double strand breaks was (until recently) an unexplored territory, both in vitro and in vivo. However, we recently discovered that expression of leukemia-associated oncogenes in hematopoietic SCs (HSCs) induces DNA damage, p53-independent p21-upregulation, DNA repair and extended self-renewal [22], suggesting that a specific cellular response to DD takes effect in normal SCs and is de-regulated (or constitutively activated) by oncogenes. In this chapter, we review recent progresses in our understanding of the DDR in stem and progenitor cells, in vivo, as well as our group's contribution to this field. DNA damage processing in SCs Adult SCs self-renew and maintain tissue homeostasis throughout the life of an individual. Therefore, it has long been speculated that they possess evolutionary features allowing them to survive and repopulate the original tissue shortly after acute insults [23]. Importantly, DD processing in SCs must ensure genome integrity for daughter SCs and downstream lineages. Indeed, the impact of damage accrued in individual SCs is potentiated through the self-renewal and differentiation processes, with possible ramifications to all levels of the developmental hierarchy. This is particularly true for highly regenerative tissues such as the skin, the gut and the hematopoietic system. The blood system hierarchy is very well characterized and comprises a small number of long-term SCs that are predominantly quiescent and which ensure the lifelong production of all the diverse hematopoietic cell types, and progenitors that proliferate and progressively differentiate. Hematopoietic stem cells (HSCs) are probably the best characterized among somatic SCs, owing to the availability of well-established cell surface markers that facilitate their purification; they can be quantitatively and qualitatively assayed with high resolution [24,25]. Mouse long-term HSC markers are particularly refined and allow purification of a population – termed LT-HSC (expressing the lin− Sca1+ cKit+ Flk2− CD34− markers) – that generates long-term reconstitution in about 30% of single cell repopulation transplants [26]. HSCs, along with other tissue-specific SCs, are equipped with a variety of cytoprotective mechanisms to ensure protection of their genomes beyond that of other cell types. For example, they possess a high ABC transporter activity that pumps genotoxic compounds out of the cell. Moreover, they experience exogenous protection because of the hypoxic niche where they reside. Additionally, they display a quiescent, metabolically inactive state that generates low levels of endogenous free radicals and reactive oxygen species [27–29]. Nevertheless, DNA lesions accumulate in SCs. So what happens once they have occurred? Mohrin and colleagues addressed this issue by using hematopoietic stem/progenitor cells (HSPCs) – defined as lin−/c-kit+/Sca-1+/Flk2− bone marrow cells – and myeloid progenitors, isolated from young

mice [30]. They found that, in agreement with earlier studies [31], these cells were more resistant than the progenitor cells to apoptosis induced by low doses of ionizing radiation (2 Gy). This unique cell intrinsic mechanism, which ensures survival of HSPCs following DNA damage, included enhanced expression of pro-survival genes (like Bcl2 and Bcl-xl) and robust induction of p53, resulting in a strong upregulation of both proapoptotic target-genes (like Bax and Puma) and p21 expression. A strong induction of p53 and of its target genes was also observed in myeloid progenitors that, in contrast, undergo apoptosis. The researchers thus hypothesized that high levels of pro-survival factors in HSPCs might limit apoptosis while supporting p21-mediated growth arrest, DNA repair and survival. Importantly, however, there are two observations by the same group that question the role of p53 in the unique response of HSCs to DNA damage. First, when HSPCs are induced to cycle through prolonged culture or treatment with the cytokine G-CSF, they are protected from ionizing radiation (IR)-mediated apoptosis in the absence of a p53-mediated response. Second, p53−/− HSPCs show increased radioresistance. Strikingly, in contrast to this study, in a companion study Milyavsky and colleagues reported that human umbilical cord blood (CB)-derived HSPCs (a fraction containing few HSCs and many MPPs, defined as linage− CD34 + CD38− CD45RA−) undergo p53-dependent apoptosis after irradiation [32]. The DDR differences seen in CB from human versus bone-marrow from mice may have a different basis. In our opinion, they most likely reflect cell-intrinsic differences between SCs at different stages of ontogeny. Indeed, human umbilical CB-derived HSCs are highly proliferative cells that are considered to be of fetal origin; their genomic integrity is expected to be highly protected in order to obtain a pool of cells able to sustain lifelong hematopoiesis in the organism and for reproduction. In contrast, bone-marrow HSCs are largely quiescent adult SCs; the main functions of these cells are to quickly respond to hematopoietic needs and provide immediate blood homeostasis [27,33]. However, a direct comparison between the studied cells is not possible because the antibodies used to purify SC and progenitor populations are different between human and mouse (being more refined in the mouse). In an attempt to elucidate the mechanisms through which HSCs process DNA damage and resolve these discrepancies, our group studied the responses elicited in vivo by X-ray treatment of wild-type and p53−/− mice [34]. We characterized the response to DNA damage in highly purified HSCs (LT-HSCs: long-term reconstituting HSCs, Lin−/cKit+/Sca-1+/Flk2−/CD34−) and in different progenitor subpopulations (ST-HSCs: short-term reconstituting HSCs, Lin−/c-Kit+/Sca-1+/Flk2−/ CD34+; MPPs: multipotent progenitors, Lin−/c-Kit+/Sca-1+/Flk2+/ CD34+; CMPs: common myeloid progenitors, Lin−/c-Kit+/Sca-1−). Strikingly, we found that, upon irradiation, LT-HSCs do not activate p53, but activate p21 independently of p53. Importantly, p21 upregulation inhibits p53 induction and prevents apoptosis. The apparent discrepancy between our data and those from Passegué and colleagues fully depends on the SC populations analyzed. HSPCs mainly include ST-HSCs (about 75%) and thus the rare LT-HSC population (about 25%) is likely overlooked. Indeed, when we analyzed purified ST-HSCs, we found p53 activation, as in other progenitor populations, namely MPPs and CMPs. Strikingly, however, while MPPs and CMPs underwent p53-dependent apoptosis, ST-HSCs were radio-resistant, as reported by Passegué and colleagues, and their enhanced resistance to X-rayinduced apoptosis was p21-dependent. Our data thus show that stem/ progenitor populations that differ for self-renewal and differentiation potential display different DDRs: LT-HSCs respond to X-irradiation with a p21-dependent inhibition of p53-activation and apoptosis; STHSCs show p53 activation and p21-dependent inhibition of apoptosis; and MPPs and CMPs undergo p53-dependent and p21-independent apoptosis. In other words, progressive loss of self-renewal correlates with a switch from a p21-dependent response that inhibits p53 functions and apoptosis to a p53-dependent response that activates p21-dependent apoptosis. This “checkpoint maturation” that

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accompanies hematopoietic cell differentiation most likely underlies the inconsistencies between our data and those reported by Passegué and colleagues. Different adult tissue-specific SCs share the same task of preserving organ functionality. We therefore studied p53 and p21 regulatory systems after X-rays in another SC compartment, namely mammary SCs (MaSCs). Also in this system, we analyzed highly purified SCs, defined by the PKH-26 label-retaining assay [35]. The purified (PKH+) MaSCs are able to reconstitute a mammary gland in about 30% of single cell repopulation transplants. Remarkably, irradiated MaSCs displayed a response to DNA damage identical to that observed in LT-HSCs, implying that the LT-HSC DDR is not unique to the hematopoietic system but conserved in SCs of different origins. Accordingly, Sotiropoulou and colleagues reported a similar response (short duration of p53 activation and resistance to apoptosis) for a population enriched in hair follicle bulge SCs (BSCs) [36]. Interestingly however, hair follicle melanocyte SCs (MSCs), that are located in the same hair follicle niche as BSCs, have a different cell autonomous response to DD: p53 is transiently activated but cells are eliminated by premature differentiation (independently of p53) [37]. Another well-known exception of SCs being resistant to DD is the intestine. Intestinal SCs (ISCs) are particularly sensitive to DD: they show enhanced p53 activation and undergo massive apoptosis upon low doses of X-rays [38,39]. Remarkably, colon SCs (CoSCs), despite sharing a similar localization at the crypt bottom, are considerably more radioresistant than ISCs [40,41]. Importantly, their radioresistance has been linked to a lower expression of p53 (and a

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higher expression of Bcl2) [42–46], strongly supporting the notion that a unique and p53-independent DDR is conserved in most adult SCs. The main outcomes of this pathway are cell survival and repair of damaged DNA. Notably, DNA repair in HSPCs and BSCs has been shown to occur by non-homologous end joining, an error-prone mechanism that is typical of quiescent cells [30,36]. As a result, chromosomal aberrations were identified in irradiated HSPCs and in their progeny, and engraftment defects were observed in secondary recipients [30]. Accordingly, using highly purified HSCs and MaSCs we found that repair of damaged DNA is incomplete, since we detected moderate levels of persistent DD several months after irradiation of wild-type LT-HSCs, and reduced self-renewal. Importantly, both effects (persistent DD after irradiation and reduced self-renewal) were exacerbated in the absence of p21, indicating that p21 regulates the cellular response to DD in SCs (HSCs and MaSCs), limiting DD accumulation and preventing exhaustion of their self-renewal capability. To our surprise, when we investigated how p21 prevents DD accrual, we discovered that p21 up-regulation after X-ray induced cell-cycle entry and expansion of the absolute numbers of LT-HSCs and MaSCs. Increased numbers of SCs after X-rays were caused by induction of symmetric self-renewing divisions in MaSCs that, mechanistically, relies on p21-dependent downregulation of p53 activity [34]. Collectively our data, along with other published studies, reveal that, following DD, SCs inactivate apoptotic responses, limit DD accumulation, maintain self-renewal and enter symmetric self-renewing divisions.

Fig. 1. DNA damage processing in stem cells. Adult SCs are resistant to DD-induced apoptosis or senescence. This event has been linked to up-regulation of p21, reduced p53 activation and enhanced expression of pro-survival genes. Additionally, p21-dependent inhibition of p53 activation and of p53 basal activity leads to cell cycle entry and symmetric selfrenewing divisions of SCs. p21 also activates DNA repair in SCs, thereby limiting accrual of DD and exhaustion of their self-renewal potential. This unique response preserves shortterm organ functionality. However, continuous DD and DD repair might favor accumulation of SCs that harbor DNA mutations, which, over a lifespan, can reduce their functional efficiency (aging) or favor transformation (cancer).

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Importantly, the outcome of this unique DDR is the expansion of a pool of functional SCs able to fulfill their role of preserving short-term tissue reconstitution (Fig. 1). Impact on aging and cancer The ability of SCs to handle DD without committing apoptosis or undergoing senescence, but rather activating a DNA repair response, might have important physiological and pathological consequences. Mammalian aging results, at least in some key aspects, from an ageassociated decline in SC functionality. A number of recent studies implicate DD repair and maintenance of genomic integrity as important mechanisms in the preservation of SC functions. These studies analyzed patients with hereditable mutations, or mouse models with engineered mutations in specific DNA repair pathways (that decrease DNA repair activities). In humans, patients with deficiencies in genomic maintenance genes display bone marrow failure syndromes (with varying degrees of cytopenia) [47–49]. Significant functional defects were detected in HSCs from mice deficient in DNA repair proteins involved in homologous recombination, mismatch repair, nucleotide excision repair or interstrand crosslink repair, such as FANCD1, MSH2, or ERCC1 [50–52]. A mouse strain with a hypomorphic mutation in DNA ligase IV, which is involved in double-strand break repair by nonhomologous end joining, showed a progressive loss in HSC numbers and functions during aging [53]. Furthermore, mice bearing a mutated Rad50 allele displayed profound bone marrow hypoplasia resulting from constitutive activation of the ATM pathway, suggesting that excess DD signaling reduces HSC numbers and/or functions [54,55]. Finally, Rossi and colleagues showed that mice with germline deficiencies in nucleotide excision repair, non-homologous end joining or telomere maintenance (XPDTTD, Ku80−/− and late-generation mTR−/− mice, respectively) displayed a premature decline in HSC functions. Most importantly, this study noted DD accumulation (in terms of γ-H2AX foci) in the LT-HSC compartment, with physiological aging even in wildtype mice [56]. Similarly, increased incidence of endogenous γ-H2AX foci was observed during human aging in peripheral blood lymphocytes and in hematopoietic stem and progenitor cells [57,58]. Together, these results are consistent with the view that endogenous DD is accumulated during physiological aging and results in decreased self-renewal of the aged SCs. Notably, as mentioned, we recently demonstrated that SCs possess specific mechanisms for the processing of the DNA damage generated by exogenous irradiation or by endogenous cellular activities, but that some damaged DNAs evade repair and accumulate over time limiting their SC self-renewal potential. Therefore, adult SCs survive DNA-damaging insults, but their imperfect DD response limits their life span. Genetically, this cellular response is dependent on p21 and independent of p53. Indeed, in the absence of p21, DD accumulation in LT-HSCs during physiological aging was significantly more pronounced than in the WT, leading to their premature exhaustion [34]. We propose that this flawed DNA repair response in SCs physiologically evolved as a mechanism of tumor suppression in these cells, as p53mediated apoptosis or senescence is suppressed. On the other hand, this response in SCs can work as a double-edged sword during the lifetime of an individual. Continuous waves of DD and DD-repair in SCs might lead to accumulation of DNA-mutations (mutator phenotype), thus favoring tumor initiation. Furthermore, expression of activated oncogenes in SCs induces DD and DD-repair activities ([22]), further increasing their propensity to accumulate DNA-mutations and progress toward full transformation. Indeed, we found that hyper-activation of p21-dependent DNA repair mechanism contributes to leukemia progression [22]. It is interesting to note that tissues in which SCs do not repair DD do not give rise to common human tumors. For instance, hair follicle melanocyte SCs that undergo premature differentiation following DD do not give rise to melanoma that, in contrast, originates from skin melanocytes. Furthermore, apoptosis of intestinal SCs upon DD might explain the rarity of intestinal

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DNA damage response in adult stem cells.

This review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span o...
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