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Biol.from2004.With permission11:1037-1043,Ltd.)MacmillanPublishers224Chapter4: DNA,Chromosomes,and Genomesadjacent nucleosomes (seeFigure 4-33). However, the most profound effect ofthe histone modifications is their ability to attract specific proteins to a stretchof chromatin that has been appropriately modified. These new proteins determine how and when genes will be expressed,as well as other biological functions. In this way, the precise structure of a domain of chromatin determines theexpressionof the genespackaged in it, and thereby the structure and function ofthe eucaryotic cell.ChromatinAcquiresAdditionalVarietyThroughthe Site-SpecificInsertionof a SmallSetof HistoneVariantsDespite the tight conservation of the amino acid sequencesof the four core histones over hundreds of millions of years, eucaryotes also contain a few varianthistones that assemble into nucleosomes.
These histones are present in muchsmaller amounts than the major histones, and they have been less well conserved over long evolutionary times. Except for histone H4, variants exist foreach of the core histones; some examples are shown in Figure 4-41.The major histones are synthesized primarily during the S phase of the cellcycle (see Figure l7-4) and assembled into nucleosomes on the daughter DNAhelices just behind the replication fork (seeFigure 5-38). In contrast, most histone variants are synthesized throughout interphase. They are often insertedinto already-formed chromatin, which requires a histone-exchangeprocess catalyzed by the ATP-dependent chromatin remodeling complexes discussed previously. These remodeling complexes contain subunits that cause them to bindboth to specific sites on chromatin and to histone chaperones that carry a particular variant.
As a result, each histone variant is inserted into chromatin in ahighly selectivemanner (seeFigure 4-30).The CovalentModificationsand the HistoneVariantsAct inConcertto Producea "HistoneCode"ThatHelpsto DetermineB i o l o g i c aFl u n c t i o nThe number of possible distinct markings on an indMdual nucleosome is enormous. Even with the recognition that some of the covalent modifications aremutually exclusive(for example,it is not possiblefor a lysine to be both acetylatedand methylated at the same time), and that other modifications are createdtogether as a set, it is clear that thousands of combinations can exist.
In addition,there is the further diversity created by nucleosomes that contain histone variants.h i s t o n ef o l dS P E C I AFLU N C T I O NH3H33t r a n s c r i p t i o n aal c t i v a t i o nCENP-Aloop insertc e n t r o m e r ef u n c t i o na n dk i n e t o c h o r ea s s e m b l yH24H2AXD N A r e p a i ra n drecombinationH2AZg e n ee x p r e s S r o n ,c h r o m o s o m es e g r e g a t i o nmacroH2At r a n s c r i p t i o n ar le p r e s s i o n ,X - c h r o m o s o m ien a c t i v a t i o nh i s t o n ef o l dFigure 4-41 The structure of somehistonevariantscomparedwith themajor histone that they replace.Thesehistonesareinsertedinto nucleosomesatspecificsiteson chromosomesbyATP-dependentchromatinremodelingenzymesthat act in concertwith histone(seeFigure4-30).ThechaperonesCENP-Avariantof histoneH3 is discussedlaterin this chapter(seeFigures4-48 to4-51); othervariantsarediscussedinChapter7.The sequencesthat arecoloreddifferentlyin eachvariantare differentfrom the correspondingsequenceof themajorhistone.(Adaptedfrom K.Sarmaand D.
Reinberg,Nat.Rev.Mol.Cell.Biol.6:139-149,2005.With permissionfromMacmillanPublishersLtd.)225THEREGULATIONOFCHROMATINSTRUCTUREZn(B)Many of the combinations appear to have a specific meaning for the cellbecausethey determine how and when the DNA packaged in the nucleosomesis accessed,leading to the histone code hlpothesis. For example, one type ofmarking signals that a stretch of chromatin has been newly replicated, anothersignals that the DNA in that chromatin has been damaged and needs repair,while many others signal when and how gene expression should take place.Small protein modules bind to specific marks, recognizing for example a trimethylated lysine 4 on histone H3 (Figure tl-42).
These modules are thought toact in concert with other modules as part of a code-readercomplex, so as toallow particular combinations of markings on chromatin to attract additionalprotein complexes that execute an appropriate biological function at the righttime (Figure 443).scaffoldorotein modulesproteinb i n d i n gt o s p e c i f i ch i s t o n em o d i f i c a t i o n son nucteosomeFigure 4-42 How each mark on anucleosomeis read.The structureof aproteinmodulethat sPecificallYonhistoneH3 trimethylatedrecognizesmodellysine4 is shown.(A)Space-fillingof an INGPHDdomainboundto ahistonetail (green,with the trimethylgroup highlightedinyellow).(B)A ribbonmodelshowinghow the N-terminalsixaminoacidsin the H3 tail arerecognized.The doshedIinesrepresenthydrogenbonds.Thisis one of manyPHDdomainsthat recognizemethylatedlysinesondifferentdomainsbind tightlyhistones;to lysineslocatedat differentpositions,betweenaand they can discriminatelysine.In amono-,di-,and tri-methylatedsimilarway,othersmallproteinmodulesspecifichistonesidechainsrecognizethat havebeen markedwith acetylgroups,phosphategrouPs,and so on.(Adaptedfrom P.V.Penaet al.,Nature03,2006.With permissionfrom442:100-1Ltd.)MacmillanPublishersc o v al e n tmodificationo n h i s t o n et a i l(mark)C O D ER E A D E RBINDSANDATTRACTSOTHERCOMPONENTSp r o t e i nc o m p l e xw i t hcatalyticactivitiesanda d d i t i o n a lb i n d i n gs i t e sFigure4-43 Schematicdiagramshowinghow the histone code could be read by acode-readercomplex.A largeproteincomplexthat containsa seriesof proteinamodules,eachof which recognizesspecifichistonemark,is schematically"code-readerillustrated(green).Thiscomplex"will bind tightlyonly to a regionof chromatinthat containsseveralof thedifferenthistonemarksthat it recognizes'Therefore,only a specificcombinationofmarkswill causethe complexto bind tochromatinand attractadditionalproteincomplexes(purple)thatcatalyzeabiolooicalfunction.226Chapter4: DNA,Chromosomes,and Genomes(A)MMRK24(B)AMAAAMlPMvrlMKS910K14IYI?rlRK1118KRKS2 3 262728modification stateMMK36K79r"meaning"Mh e t e r o c h r o m a t i fno r m a t i o n ,g e n es i l e n c i n gN9MArlg e n ee x p r e S s r o nKK49PAt lSK10g e n ee x p r e S S t o n14MIK27s i l e n c i n go f H o x g e n e s ,X c h r o m o s o m ei n a c t i v a t i o nThe marks on nucleosomes due to covalent additions to histones aredynamic, being constantly removed and added at rates that depend on theirchromosomal locations.
Because the histone tails extend outward from thenucleosome core and are likely to be accessibleeven when chromatin is condensed, they would seem to provide an especially suitable format for creatingmarks in a form that can be readily altered as a cell's needs change. Althoughmuch remains to be learned about the meaning of the many different histonecode combinations, a few well-studied examples of the information that can beencoded in the histone H3 tail are listed in Figure 4-44.proteinsCanSpreadA Complexof Code-readerand Code-writerSpecificChromatinModificationsfor LongDistancesAlongaCh r o m o s o m eThe phenomenon of position effect variegation described previously requiresthat at least some modified forms of chromatin have the ability to ipreud fotsubstantial distances along a chromosomal DNA molecule (see Figure 4-36).How is this possible?The enzymes that modify (or remove modifications from) the histones innucleosomes are part of multisubunit complexes.They can initially be broughtto a particular region of chromatin by one of the sequence-specificDNA-binding proteins (gene regulatory proteins) discussedin chapters 6 and 7 (for a specific example, see Figure 7-87).
But after a modifying enzyme "writes" its markon one or a few neighboring nucleosomes,events that resemble a chain reactioncan ensue. In this case,the "code-writer" enzyme works in concert with a codereader protein located in the same protein complex. This second protein contains a code-reader module that recognizes the mark and binds tightly to thenewly modified nucleosome (see Figure 4-42), positioning its attached writerenzyme near an adjacent nucleosome. Through many such read-write cycles,the reader protein can carry the writer enzyrne along the DNA-spreading themark in a hand-over-hand manner along the chromosome (Figure 4-45).In reality, the process is more complicated than the scheme just described.Both readers and writers are part of a protein complex that is likely to containFigure 4-44 Somespecificmeaningsofthe histonecode.(A)The modificationson the histoneH3 N-terminaltail areshown,repeatedfrom Figure4-39.(B)The H3 tail can be markedby differentcombinationsof modificationsthatconveya specificmeaningto the stretchof chromatinwherethis combinationoccurs.Onlya few of the meaningsareknown,includingthe four examplesshown.Tofocuson just one example,thetrimethylationof lysine9 attractstheproteinHP1,heterochromatin-specificwhichinducesa spreadingwaveoffurtherlysine9 trimethylationfollowedby furtherHP1binding,accordingto thegeneralschemethat will be illustratedshortly(seeFigure4-46).
Not shown isthe fact that,asjust implied(seeFigure4-43),readingthe histonecodegenerallyinvolvesthe joint recognitionof marksatothersiteson the nucleosomealongwiththe indicatedH3 tail recognition.Inaddition,specificlevelsof methylation(mono-,di-,or tri-methylgroups)arerequired,as in Figure4-42.THEREGULATIONOFCHROMATINSTRUCTUREg e n e r e g u l a t o r yp r o t e i nc o d e - r e a d epr r o t e i nh i s t o n em o d i fi c a t i o n( m a r k )multiple readers and writers, and to require multiple marks on the nucleosometo spread.
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