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Y. nucleostemin Robert on page new a Turning COMMENTARY ß Ato o orsodne([email protected]) USA. correspondence 77030, for TX *Author and Houston, Biosciences Center, of Science Institute Health Biology, A&M Cell Texas Stem Technology, and Cancer for Center of point of the outcome an manner cell-context-dependent the to represents a that in up cells, surprise varies occur no often happened of perturbation as they population have come should a do that it or it measurement, Or, events be cell first? of study, single cell-centered comes integration a any which on in phenotypes to readout so, based lead the ribosomal one if As Does and, independently? non- perturbation. and gene other the of damage) the event single between DNA a following relationship (e.g. associative ribosomal non- versus the determine other to challenging (or causative more maintenance link ever it emerging genome makes events) The and ribosomal 2014). nucleolus al., the as et between well dual as (Antoniali repair play synthesis and to response ribosomal damage reported DNA the been regulating have in roles that ribosomal organelle or intranuclear nucleolar years, recent well-recognized within Increasingly, biogenesis. ribosome a in functions is nucleolus The Introduction cell Stem Nucleolus, Self-renewal, , synthesis, damage, Ribosomal GNL3, DNA Nucleostemin, arrest, cycle Cell WORDS: KEY events phenotype maintenance cells. genome biological stem the molecular in of cell understanding program underlying new any a signifies of the also appearance and the of with complexity associated the nucleostemin of story highlights The multi- perceived. as previously be been not has might as tasking this that suggest and reconciled nucleostemin be explains surrounding can that observations model contradictory a many propose the how I Commentary, this In nucleostemin- cells. of depleted profile arrest cycle cell that of the dependency and p53 activity nucleostemin the argues regarding reports conflicting Furthermore, which been perturbation. have ribosomal in there to damage studies, leads then DNA is that of cells recent nucleostemin phase event S primary of from a role triggers depletion ribosomal evidence nucleostemin a card- As by ribosomes. the be, of in might refuted biogenesis the function this the might – in as it nucleolus tantalizing that the nucleostemin notion of event the of carrying to presence led in has predominant nucleostemin nucleolus of its the Since role cells. cancer discovery, and unexpected stem of an integrity genome the to safeguarding GTP- pointed recently genome nucleolar guanine-nucleotide- studies have Several of the species). as invertebrate in GNL3, known result is 3, protein-like (also binding factor a nucleostemin self-renewal as protein binding key damage One DNA self- replication. to incurring ability their without in embedded is renew cells stem of trait quintessential A ABSTRACT 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,38–81doi:10.1242/jcs.154054 3885–3891 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. tmclsadcne cells. cancer of and maintenance self-renewal cells the stem read of perceived understanding commonly be new than a might ways reveal subtle and function more perturbed in cells one by differently how highlight invertebrate to as in species) known GNL3, (also nucleostemin 3, with protein-like journey guanine-nucleotide-binding nucleostemin. our protein uses this on and nucleolar debates molecule existing simply the three resolve is to protein’, are attempts which multi-tasking Commentary This of a variations example of function good those more are a ‘one indirectly, often yet or as too directly interpreted either However, affected, pathways considered. explained logically the be all can but once first, at paradoxical seem might that ulotmnwsdsoee eas fishg xrsinin expression high its of because discovered was Nucleostemin mysteries and History euetlmr aaetruhmdfcto ftlmrcrepeat to telomeric able non-telomeric of is modification and through nucleostemin damage that telomeres telomere shown reduce the has on study reached. been One nucleostemin damage . be have of DNA mechanism studies to reducing molecular several considerable in remains the years, reveal Despite subject two that past published this clear. the on within less However, consensus a is interest, functions al., 2012). et Bishop, nucleostemin Tamase and 2004; 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Journal of Cell Science h ulou notencepam hssde nraeof increase sudden This if nucleoplasm. p53, the activate into released nucleolar nucleolus is might under nucleostemin the disassembled mitosis, ATM–checkpoint which during is or nucleolus and pathways, stress the Rad3-related When (Chk2) (Chk1) and available. arrest, 2 replication- 1 telangiectasia phase kinase S ataxia triggers kinase to the leads nucleostemin (ATR)–checkpoint then through which of possibly damage, loss DNA associated nucleoli, intact COMMENTARY xml,nnhmlgu n-onn NE)i sdby used for is 3890 status, (NHEJ) mitotic end-joining their on non-homologous depending different example, its on repair rely make also for might damage cells mechanisms nucleostemin stem DNA surprisingly, which Not of area in. efficiency contribution an through the – the machinery suppress promote insults repair or that genotoxic pathway mechanisms apoptotic extrinsic protective might cells cancer, specialized These or 2008). breast engaging al., et cell-intrinsic in Diehn Li 2006; 2006; CSCs al., survive al., et as Jordan et 2009; 2010) (Bao well al., al., et multiforme as et glioblastoma (Sotiropoulou cells, and cells leukemia stem stem mammary follicle stem (Rachidi hair and cells hematopoietic stem 2007), adult epidermal al., cells for 2010), et al., stem shown of et been of an (Mohrin lack has (HSCs) types cells as the by more live, or comparison, to Their mechanistically By network choose damage. activity. pro-apoptotic driven repair the DNA DNA be in response activity might in enhanced behavior suicide and preferentially commit altruistic 2006) that types al., damage to cell et those choose among DNA (Finlan are cells cells stem under stem intestinal cell. basal the cells interfollicular of origins 2010), stem tissue the in factor of lie which might So answer behavior The 2011). damaged conditions? to repair al., the and et self- to cell-intrinsic regard (Blanpain respond dictates to to efficiently choose With or more might from good DNA limited greater cells 2008). a stem for and production damaged Scadden, sacrifice mitotically repair, stress, and and a species response replicative (Orford stress, avoids oxygen metabolism low oxidative that with minimize reactive state microenvironment to quiescent specific levels been have a goal oxygen this including achieve help reduction, proposed, might damage that to mechanisms regard With several lethality, incidence. cancer sensitivity, elevated embryonic radiation and and UV cell aging, increased stem deficiency, to premature hematopoietic traced be including a can these and that As of dysfunction, phenotypes response many in quality. in damage result defects pristine often DNA maintenance, proteins cell most the stem the in of of proteins importance at integrity repair the kept the to that be testament sense must perfect genome stem adult makes their that and it organogenesis Given homeostasis, embryonic in replication. tissue cornerstone genome the form by repair cells caused to active equipped damage differentially mitotically that, be DNA might progeny, suggests cells progenitor cells, differentiated or and stem stem their expression cancerous with established and compared its normal in with DNA importance conjunction increased in of protection, result in a arrest. cycle depletion be cell apparent nucleostemin fact subsequent and The in upon damage might nucleostemin. seen cells by is mammalian that not been defect has and activity ribosomal GNL3L this by in cells, repair. role mammalian inherited DNA a in have in synthesis, and indeed function ribosomal with might its nucleostemin interact invertebrate of to Although it independently allows MDM2 nucleoplasm stabilize the in nucleostemin hsnwyrvae ciiyo ulotmni genome in nucleostemin of activity revealed newly This odboddrvdhmnebyncHC Mlasye al., et (Milyavsky HSCs embryonic human Cord-blood-derived nmasse en from rtciemcaim nsl-eeigcls ulotmndoes alone. nucleostemin stand cells, not self-renewing in of mechanisms genome- 2013). specialized of phenotype protective idea al., the the supporting to comes et resembles it when extent Indeed, (Meng some mice to nucleostemin-knockout which nestin-driven 2014), al., (Pao bulb et olfactory and agenesis cerebellum severe hippocampus, neocortex, in the results of epithelium neural developing this the of in Deletion gene 1995). al., et (Lane progenitors cancer proliferative highly contains which neuroepithelium, most embryonic Breast the is spindle, in mitotic expressed highly and centrosome cells. functions the repair, with damage suppressor DNA tumor hyperactive in a (BRCA1), mitotically 1 gene susceptibility by in particular used in show pathway members enrichment repair Some and is response 2010). damage DNA al., recombination core the et homologous (Mohrin HSCs active and mitotically HSCs quiescent ucini h ignsso iooe h eotdefc of cells effect mammalian reported in the synthesis might of ribosome, rRNA nucleostemin on conditions of depletion biogenesis under invertebrate nucleostemin the MDM2 in Although function stabilizing stress. an in and nucleolar constitutive damage activity and DNA replicative primary induced against a logical safeguarding exercises is in it nucleostemin activity consideration, that in think discussed been to have that all Taking Conclusion u . a,M . hn .Q,W,W,Mhlna,S n aaudrm D. Balasundaram, and S. Mahalingam, W., Wu, Q., X. Chen, R., M. Rao, Qian, X., Du, N., A. Kulp, J., M. Dorie, T., Kalisky, A., N. Lobo, W., R. Cho, M., Diehn, H. Lu, and X. X. Sun, S., M. B. Dai, J. Lazaro, and D. J. Iglehart, S., Passegue A. and Calkins, A. P. Sotiropoulou, M., Mohrin, C., Blanpain, W., Wurst, T., Floss, M., Maetens, S., Clercq, De M., Nichane, C., Beekman, Dewhirst, B., A. Hjelmeland, Q., Shi, Y., Hao, E., R. McLendon, and Q., C. Wu, S., G. Bao, Kopen, C., Hughes, D., Gaupp, R., Wilkinson, K., Hill, M., Baddoo, G. Tell, and M. Poletto, L., Lirussi, G., Antoniali, months. 12 after release References for PMC the in and Deposited Award; Health. Incentive of Cancer Council National Institutes Research the National Cancer by A&M supported Texas was cited a work Institute; current and recent author’s The Funding interests. competing no declares author The interests Competing D. group Ronald and his support, in insight. unwavering members his her current for for Tsai Y. and McKay S. previous work, the hard all dedicated their thank for to like would author The self-renewal. of Acknowledgements understanding the our life in maintaining the as in in well chapter as function new nucleostemin a its signifies of genome of cell replicating to discovery of secondarily integrity The occurs that arrest. event late cycle a represent rather might 20) h oooospttv Tae r1 rmfsinyatadthe and yeast fission from Grn1p GTPases putative homologous The cells. (2006). stem al. cancer et in M. radioresistance Wong, E., and 780-783. L. levels Ailles, species S., oxygen J. MDM2. 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Mol. 20) bratepeso fnucleostemin of expression Aberrant (2008). 20) vltoaiycnevdrl of role conserved Evolutionarily (2006). 26 20) loase el promote cells stem Glioma (2006). 9291-9301. , .Cl.Biochem. Cell. J. 20) soito freactive of Association (2009). 21) N damage-induced DNA (2013). 21) mrigrlso the of roles Emerging (2014). uli cd Res. Acids Nucleic elSe Cell ,E. ´, 89 nixd Redox Antioxid. 1235-1249. , 21) DNA- (2011). Nature o.Cell. Mol. 8 16-29. , Nature 458 41 , ,

Journal of Cell Science orn . ore . lxne,D,Wr,M . ar-osn . eBeau, Le K., Barry-Holson, R., M. Warr, D., Alexander, E., Bourke, F., M., Mohrin, Notta, O., Tabach, M., Komosa, M., Trottier, I., O. Gan, M., Milyavsky, Y. R. Tsai, and S.-Y. Lin, S., Lee, K., J. Hsu, G., Y. Peng, T., R. Lin, L., Meng, Tsai, and T. Lin, L., Meng, Y. R. Tsai, and Q. Zhu, Y. L., R. Meng, Tsai, and H. Yasumoto, L., Meng, Y. Xu, and Z. Zhang, Y. R., R. Liu, Tsai, and T. Pederson, J., L. Wu, L., Meng, T., Lin, Y. R. Tsai, and Y. J. M. R. Finegold, Tsai, C.-Y., Peng, and W., F., Ibrahim, Y. T., M. Lin, Li, Wu, L., K., Meng, C. T., Osborne, Lin, C., Gutierrez, J., Huang, T., M. P. Lewis, Leder, X., and A. Li, C. Kozak, S., M. Lyu, A., Elson, C., Deng, F., T. Lane, V. Reinke, and M. M. Montan Kudron, M., Orlov, E., E. Crouch, M., M. Kruhlak, Noble, and L. M. Guzman, T., C. Jordan, COMMENTARY aso . rnea,S,Tos . aia,R . olre,D n Hurt, and D. Tollervey, G., R. Manikas, M., Thoms, S., Granneman, Y., Matsuo, K. 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Z. role human Konovalova, apoptosis-independent in K., response an Eppert, damage G., DNA K. distinctive Hermans, E., the Lechman, maintains that cells. mechanism progenitor and essential 11415-11420. stem cell an of stability and reveals genomic progression deletion Nucleostemin G2-M promotes and MDM2 survival. stabilizes nucleostemin mechanisms. protein-specific versus 27 common proteins: family nucleoplasm. and 5124-5136. nucleolus between partitioning nucleostemin ibosome and protection genome in functions distinct respectively. exercise synthesis, GNL3L and regeneration. hepatocytes and dividing of development integrity liver genome mouse the during maintaining in nucleostemin of role cells. tumor mammary al. nucleostemin-enriched et C. chemotherapy. 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