A Survivor Hits the Breaks

Bcl2 is the founding member of a family of proteins that regulates apoptosis by controlling mitochondrial outer membrane integrity. In this issue of Molecular Cell, Wang et al. (2008) propose another function for Bcl2: the inhibition of DNA repair by
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   A Survivor Hits the Breaks Douglas R. Green 1, * and Peter J. McKinnon 2 1 Department of Immunology 2 Department of Genetics and Tumor BiologySt. Jude Children’s Research Hospital, Memphis, TN 38105, USA *Correspondence: 10.1016/j.molcel.2008.02.003 Bcl2 is the founding member of a family of proteins that regulates apoptosis by controlling mitochondrialouter membrane integrity. In this issue of   Molecular Cell  , Wang et al. (2008) propose another function for Bcl2: the inhibition of DNA repair by nonhomologous end-joining. There is a Native American story abouta man whose petition to the godsfor eter-nal life is granted. But in the way of suchthings he forgot to stipulate conditions,and he aged and aged until, shrunkenand wrinkled, he became a grasshopper. Aside from the improbable entymologicalphenomenon,thereareparallelsherewitha paper in this issue of   Molecular Cell  ( Wang et al., 2008 ): a set of observationsthat raise puzzling and unexpected ques-tions about a form of cellular immortalityand its links to DNA repair.Wang et al. (2008) describe an ability of Bcl2, the archetypal antiapoptotic pro-tein, to block DNA repair by the processof nonhomologous end-joining (NHEJ).The effect is distinct from that of the anti-apoptotic mechanism, which involvesinteractions with other proapoptotic Bcl2family proteins to prevent the permeabili-zation of the mitochondrial outer mem-brane and thereby prevent apoptosisvia the mitochondrial pathway ( Green,2007 ). This antiapoptotic activity involvesfour ‘‘Bcl2 homology’’ regions in the mol-ecule,butonlytwooftheseareinvolvedinthe inhibitory effect on NHEJ ( Figure 1 ).DNA double-strand breaks (DSBs) area particularly deleterious form of DNA damage and if left unrepaired can resultin cancer-causing mutations or promoteaging. DNA DSBs occur as a result of oxidative metabolism, DNA replication, orV(D)J recombination during immune sys-tem maturation; they also can arise fromexogenous agents such as ionizing radia-tion. DNA DSB repair is achieved throughtwo specific DNA repair pathways: NHEJand homologous recombination (HR)repair ( Wyman and Kanaar, 2006 ). HRis cell-cycle dependent and requiresa homologous sister chromatid to ensureerror-free DNA repair. In contrast, NHEJfacilitates the direct repair of damagednonhomologousDNAends.NHEJdirectlymodifiestheendsof a DSBtobecompat-ible for ligation and is therefore the pre-dominant pathway for repairing DSBs innoncycling mammalian cells, where a ho-mologoustemplateis notreadilyavailable( Phillips and McKinnon, 2007 ). This directprocessing of DNA ends is an effectiveway to rejoin DNA breaks and providesthecellwithareadymeanstomaintaincel-lular homeostasis after DNA damage.NHEJ involves a set of core com-ponents comprising the Ku complex (aheterodimeric protein complex of Ku70and Ku80), the DNA-dependent proteinkinase (DNA-PKcs), Cernunnos/XLF, andthe DNA ligase IV/Xrcc4 complex, whichtogether coordinate rejoining of brokenDNA ends ( Wyman and Kanaar, 2006 ).Mice in which any of these componentshave been inactivated are radiosensitive,immune deficient, and prone to cancer.The initial step in NHEJ is recognition of the DNA strand breaks by the Ku com-plex, a toroidal protein complex that canaccess and envelop DNA at the breaksite. This provides a DNA-protein inter-face that can assemble the other NHEJcomponents and enhance the efficacy of DNA repair. Thus, the Ku complex is criti-calforefficientNHEJ, andits perturbationcan compromise this DNA DSB repairpathway. It is the Ku70 component of thiscomplexthat appearstobethe targetof Bcl2 in the nucleus to inhibit NHEJ( Wang et al., 2008 ). However, Ku70 ishighly abundant, and it remains to beseen if there is sufficient Bcl2 in the nu-cleustoeffectively sequesterthiscompo-nent or if the complex with Bcl2 takes ondominant inhibitory activity.These observations might help to ex-plain some intriguing phenomena, suchaswhycancersthatarecausedbyconsti-tutive Bcl2 expression, e.g. follicular lym-phoma, can be treated by radiotherapy.They could also explain the curious ex-pression pattern of Bcl2 during B cell de-velopment;pro-Bcellsexpresshighlevelsof Bcl2, but when V(D)J rearrangementcommences in the pre-B cell stage, Bcl2disappears and does not reappear untilthe B cells mature. That is, Bcl2 is gonewhenNHEJisrequiredforDNArearrange-ment essential to B cell development.Wang et al. (2008) also suggest thattheir findings explain Bcl2-driven onco-genesis, which contributes not only toantiapoptotic signaling but also perhapsto genomic instability due to NHEJ inhibi-tion. Knockout of any NHEJ componentcanindeed result inspontaneous cancers(in conjunction with another mutation,notably loss of p53 function). However,transgene-driven Bcl2 expression inmicegenerallydoesnot,unlesscombinedwith another oncogene, such as c-Myc.DNA DSBs cause cell-cycle arrest andapoptosis via engaging p53, but tumorsexpressingBcl2tendnottolosep53func-tion (even if Bcl2 would block the apopto-sis, onewould expect thatp53losswouldavoid the cell-cycle arrest). These obser-vations are not entirely consistent witha model that predicts, as Wang and col-leagues do, that Bcl2 should promotecancerbybothblocking NHEJandblock-ing apoptosis downstream of p53.Therefore, although Bcl2-dependentNHEJ inhibition is a robust phenomenon,it might not contribute to oncogenesis. A deeper issue is this: why would a mecha-nism whereby cell survival is linked toNHEJ inhibition be sustained in the face Molecular Cell  29 , February 29, 2008 ª 2008 Elsevier Inc.  411 Molecular Cell Previews  of selection (especially if it promoted can-cer)? We propose another scenario. Sug-gestive evidence exists that retroviralinsertion depends on NHEJ ( Izsvak et al.,2004; Skalka and Katz, 2005 ). If retrovi-ruses were to infect a cell that happenedto express Bcl2, any defensive apoptoticresponsetotheviruswouldfailandthein-fectionwouldsucceed.ByblockingNHEJincellsexpressingBcl2,retroviralintegra-tion would be reduced. Of course, thishypothesis is readily testable.This effect might not be restricted toretroviruses. Early observations on Bcl2suggested that this molecule can causecell-cycle arrest (or delay), although forthe most part, this finding was likely tobe an artifact of cell survival (as cellsthat would have died due to limitinggrowth factors persisted but could notenter the cell cycle until their metabolicreserves were fully restored [Rathmell,et al., 2000]). However, one of theseobservations was intriguing (and unlikelytobeexplainedbythesameartifact):fibro-blaststhatweretransducedwithaBcl2ex-pression construct failed to grow ( Huang,et al., 1997 ). The experiment requiredstable expression of the construct andexpression of a selection marker. Theseresults could be explained if Bcl2 blockedNHEJ involved in integration of the trans-duced DNA. And if so, another aspect of these observations becomes particularlyintriguing: Bcl2 harboring a substitution attyrosine 28 (Y28F) did not show this inhib-itory effect, but it sustained antiapoptoticactivity. Y28 is in the proximity of one of the regions required for the Bcl2/Ku70interaction and NHEJ inhibition. It will beinterestingtodetermineifthisresidueisre-quired for the observed inhibitory effects.The ability of Bcl2 to modulate DNA re-pair might extend beyond NHEJ, as it ap-parentlycansuppressanotherDNArepairpathway, mismatch repair (MMR) ( Houet al., 2007 ). As for NHEJ and the Bcl2/ Ku70 interaction, the BH4 domain is re-quired for Bcl2 to modulate MMR, in thiscaseby binding the keyMMRcomponentMSH6. Is itlikely that Bcl2 not only acts atthemitochondriatopreventapoptosisbutalso restricts DNA repair by these differ-ent mechanisms? Bcl2 has also beenimplicated in other cellular functions, in-cluding regulating the IP3 receptor thatcontrols calcium efflux from the endo-plasmic reticulum and regulating autoph-agy through Beclin-1 binding. But this iswhat Bcl2 does: sequesters proteins tocontrol intracellular processes. Perhapswe are only seeing a part of a network of biological responses that are integratedby Bcl2, acting as a node. How thesemight make sense in a physiological set-ting is a challenge facing us.Of course, many more questions arisefrom these considerations. What regu-lates this activity of Bcl2 and its nuclearlocalization? Do other antiapoptotic Bcl2family members, such as Bcl-xL, Mcl-1,and A1, block NHEJ (and, perhaps, viralintegration)? Do antiapoptotic viral homo-logsofBcl2blockapoptosiswithoutinter-fering with NHEJ? Immortality, it seems,comes at a cost, but understanding whywe pay the price will be interesting. REFERENCES Green, D.R. (2007). Cancer Cell  12 , 97–99.Hou, Y., Gao, F., Wang, Q., Zhao, J., Flagg, T.,Zhang, Y., and Deng, X. (2007). J. Biol. Chem.  282 , 9279–9287.Huang, D.C., O’Reilly, L.A., Strasser, A., and Cory,S. (1997). EMBO J.  16 , 4628–4638.Izsvak,Z.,Stuwe,E.E.,Fiedler,D.,Katzer,A.,Jeggo,P.A., and Ivics, Z. (2004). Mol. Cell  13 , 279–290.Phillips, E.R., and McKinnon, P.J. (2007). Onco-gene  26 , 7799–7808.Rathmell, J.C., Vander Heiden, M.G., Harris, M.H.,Frauwirth, K.A., and Thompson, C.B. (2000). Mol.Cell  6 , 683–692.Skalka, A.M., and Katz, R.A. (2005). Cell DeathDiffer.  12 , 971–978.Wang, Q., Gao, F., May, W.S., Zhang, Y., Flagg,T., and Deng, X. (2008). Mol. Cell  29 , this issue,488–498.Wyman, C., and Kanaar, R. (2006). Annu. Rev.Genet.  40 , 363–383. Figure 1. Bcl2 Blocks DNA Repair by NHEJ The model proposed byWangetal.(2008)suggeststhatnuclearBcl2 bindsandsequestersthe abundantKu70 protein to prevent assembly of the NHEJ complex on DNA double-strand breaks. This binding andNHEJ inhibition are dependent on the BH1 and BH4 domains of Bcl2 (shown in the model in blue, BH4 onthe left) and not the BH2 and BH3 domains (shown in red), which arerequired for the antiapoptotic effectsof the protein. 412  Molecular Cell  29 , February 29, 2008 ª 2008 Elsevier Inc. Molecular Cell Previews
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