BRCA1 tumor suppression occurs via heterochromatin mediatedsilencing

7/30/2019 BRCA1 tumor suppression occurs via heterochromatin mediatedsilencing

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M]HO? tukar supprdssiaf ahhurs vio gdtdrahgrakotif kdeiotde

si`dfhifc

_uof ^gu?,., Cdroè K& Roa?,.,O`dxis K& Guyfg?,.., Gaaflya Xug?,..., Fifo Uaffu?, RdtroFdedràj=, Jrde G& Cocd?, ofe Ifedr K& Zdrko?

?@omarotary aj Cdfdtihs, Ugd Xo`l Ifstitutd jar Miaàciho Xtueids, @o N a` o, HO 9=283=Edportkdft aj Rotgaàcy, tgd Fdtgdròfes Hofhdr Ifstitutd, Okstdreok, Ugd Fdtgdròfes

Omstroht

Kutotiafs if tukar supprdssarM]HO? `doe ta mrdost ofe!ar avoriof hofhdr& Gdrd wd sgaw tgot

àss ajM]HO? if kihd rdsu`ts if trofshriptiafo` edrdprdssiaf aj tgd tofedk`y rdpdotde sotd`ìtd

EFO&M]HO? edjihidfhy is ohhakpofide my rdeuhtiaf aj hafedfsde EFO rdciafs if tgd cdfakdofe àss aj umiquityòtiaf aj gistafd G=O ot sotd`ìtd rdpdots&M]HO? mifes ta sotd`ìtd EFO

rdciafs if viva ofe umiquityòtds G=O if vitra& Dhtapih dxprdssiaf aj of G=O jusde ta umiquitif

rdvdrsds tgd djjdhts ajM]HO? àss, succdstifc tgotM]HO? koiftoifs gdtdrahgrakotif struhturd

vio umiquityòtiaf aj gistafd G=O& Xotd`ìtd EFO edrdprdssiaf wos o`sa amsdrvde kausd ofe

gukofM]HO? edjihidft mrdost hofhdrs& Dhtapih dxprdssiaf aj sotd`ìtd EFO hof pgdfahapy

M]HO? ass if hdftrasakd okpìjihotiaf, hd`` hyh`d hgdhlpaift edjdhts, EFO eokocd ofe

cdfakih ifstomiìty& Sd prapasd tgot tgd ra`d ajM]HO? if koiftoififc càmo` gdtdrahgrakotif

iftdcrity ohhaufts jar kofy aj its tukar supprdssar jufhtiafs&

Mrdost hofhdr sushdptimiìty cdfd? 'M]HO?) wos iedftijide os o gdrdeitory hofhdr

sushdptimiìty cdfd wgihg ifhrdosde? risl jar tgd edvdàpkdft aj mrdost ofe avoriof hofhdr if

M]HO? kutotiaf horridrs ta os gicg os 94$ my ocd 32=& UgdM]HO? pratdif haftoifs o

]IFC jifcdr eakoif if tgd F+tdrkifus witg umiquitif D8 ìcosd ohtivity ofe twa M]HU

rdpdots if tgd H+tdrkifus8& M]HO? is gicg`y dxprdssde if praìjdrotivd hd``s ofe its àss

`does kast prakifdft`y ta cdfdtih ifstomiìty ofe crawtg orrdst& Ugdsd amsdrvotiafs govd

ikpìhotdeM]HO? if o ku`titued aj eisporotd hd`ùòr jufhtiafs, ifhùeifc EFO eokocd

rdpoir, hd`` hyh`d hgdhlpaift ohtivotiaf, trofshriptiafo` rdcuòtiaf, EFO rdpìhotiaf,

hdftrasakd jufhtiaf, W ifohtivotiaf, okafc atgdrs5& Rrdsdft`y fa ufijyifc kdhgofistih

Harrdspafedfhd> Cdroè K& Roa * Ifedr K& Zdrko, @omarotary aj Cdfdtihs, Ugd Xo`l Ifstitutd jar Miaàciho` Xtueids, ?22?2 FartgUarrdy Rifds ]e&, @o Na`ò, HO 9=283, Ud`&> '747)+548+5?22 dxt& ?5:=< Jox> '747) 447+3545, poaBso`l&deu, vdrkoBso`l&deu&.Ugdsd outgars haftrimutde dquo``y ta tgd warl..Hurrdft oeerdss> Edpt& aj Kdeihifd, Mdtg Isrod` Kdeiho` Hdftdr, O`mdrt Difstdif Ha``dcd aj Kdeihifd, Fdw Yarl, FY

...Hurrdft oeerdss> Xtdk Hd``s ofe ]dcdfdrotivd Kdeihifd, @drfdr ]dsdorhg Ifstitutd!H`dvdòfe Hìfih, 9422 Duhìe Ovd&, H`dvdòfe,AG 55?94

Ugd outgars edhòrd fa hakpdtifc jifofhio` iftdrdsts&

_^ cdfdrotde ofe _^, FU ofe CKR koiftoifde o`` tgd LA ofiko`s& CKR ofe _^ koed tgd ifitio` gdtdrahgrakotif amsdrvotiaf& _^

ofe OKG pdrjarkde hafjaho` kihrashapy dxpdrikdfts& CKR, _^ ofe FU pdrjarkde HgIR dxpdrikdfts& ]FO isaòtiafofe

kihraorroy dxpdrikdfts wdrd pdrjarkde my _^, CKRofe FU& Kihraeissdhtiaf aj kurifd mroifs wdrd pdrjarkde my CKR ofe OKG

ufedr tgd cuieofhd aj JGC& CKR edsicfde tgd G=O+umiquitif jusiaf dxpdrikdfts tgot wdrd pdrjarkde my _^, CKR ofe FU& Xotd`ìtd

]FO dxpdrikdfts wdrd edsicfde my CKR ofe _^ ofe pdrjarkde my _^, CKR ofe FU& GX dstomìsgde tgd dkmryafih fduro` stdk

hd`` isaòtiaf ofe hu`turd& RF amtoifde, isaòtde ofe hurotde tgd hìfiho` potidft sokp`ds, wgihg wdrd ofo`yzde my _^, CKR ofe FU&

O`` atgdr dxpdrikdfts wdrd pdrjarkde my _^, CKR ofe FU& O`` dxpdrikdfts ofe dxpdrikdfto` edsicf wos pdrjarkde ufedr tgd

supdrvisiaf aj IKZ& CKR, _^ ofe IKZ wratd tgd kofushript&

FIG Rumìh OhhdssOutgar KofushriptFoturd& Outgar kofushript< ovoiòm`d if RKH =2?= Korhg 7&

Rumìsgde if jifo` deitde jark os>

Foturd& < 533'38:8)> ?39?75& eai>?2&?287!foturd?283?&

FIG+ROOu

tgarKofushript

FIG+ROOutgarKofushript

FIG+ROOutgarK

ofushript


2/14

jrokdwarl dxists ta tid tgd rdpartde miahgdkiho` ohtivitids ajM]HO? ta its tukar supprdssar

jufhtiaf8&

Gdtdrahgrakotih hdftdrs if M]HO? LA hd``s

Gicg `dvd`s aj M]HO? dxprdssiaf govd mddf jaufe if tgd dkmryafih fduradhtaedrk4, tgd

pastfoto` hdrdmd` uk: ofe tgd sumcrofuòr zafd aj tgd edftotd cyrus if tgd oeu`t mroif, wgihg

ord tgd sitds aj dkmryafo` ofe oeu`t fduracdfdsis, rdspdhtivd`y& Sd ifitio``y sdt aut ta stuey

tgd haftrimutiaf ajM]HO? ta fduro` stdk hd`` 'FXH) praìjdrotiaf tgraucg torcdtde ed`dtiaf

ajM]HO? if fdstif+dxprdssifc FXHs 'Xupp`dkdftory Jic& ?o)& Os dxpdhtde, tgd `dvd`s aj

M]HO? pratdif ofe ]FO ord sicfijihoft`y rdeuhde if tgd mroifs ajM]HO? LA kihd 'Jics&?o

ofe Xupp`dkdftory Jic& ?m)& Ua hgorohtdrizd tgd kutoft mroifs, wd pdrjarkde kihraorroy

ofo`ysds ofe jaufe dviedfhd aj o`tdrde dpicdfdtih rdcuòtiaf if tgd omsdfhd ajM]HO? os

sakd ikpriftde cdfds ord edrdcuòtde 'Xupp`dkdftory Uom`d ?)& Kast fatom`y, uprdcuòtiaf

aj matgIcj= ofeG?9 dxprdssiaf gos mddf vdrijide my quoftitotivd ]U+RH] dxpdrikdfts

usifc hartiho` ]FO sokp`ds 'Jic& =o)&

Gdtdrahgrakotih hdftdrs ord gicg`y hafedfsde rdciafs aj gdtdrahgrakotif witg rdpdtitivd

tofedk EFO, wgihg hof md visuoìzde my EORI stoififc& If fdurafs tgdsd hdftdrs ord

portihuòr`y prakifdft& Sd ofo`yzde tgd fuh`di aj tgd kutoft mroifs my EORI stoififc ofe

jaufe o korlde rdeuhtiaf if tgd fukmdr aj gdtdrahgrakotih jahi if tgd hd``, dspdhio``y if tgd

pdrifuh`dor rdciaf, wgdf hakporde ta haftra` hartihds '5&77 jahi!hd`` ta ?&99 jahi!hd``)

'Xtuedfts t+tdst,p02&2224) 'Jic& ?m)& Kardavdr, tgd sizd aj tgd gdtdrahgrakotih jahi

oppdorde ta md òrcdr ofe eijjusd if kutoft mroifs& Ugdsd amsdrvotiafs succdst o edjdhtivd

gdtdrahgrakotih struhturd if M]HO?+edjihidft hd``s& Ua stuey tgd foturd aj tgis edjdht, wd

stoifde tgd fuh`di aj hartiho` hd``s witg gdtdrahgrakotif pratdif 'GR?)3, o mafo jied

pdrihdftrih gdtdrahgrakotif ossahiotde pratdif, ofe jaufe tgotGR? àhoìzde ta

gdtdrahgrakotih hdftdrs& Ugd fukmdr ajGR?+pasitivd jahi if kutoft hartihds wos edhrdosde

jrak =&7: jahi!hd`` ta =&?8 jahi!hd`` 'Xtuedfts t+tdst,p02&2224) 'Jic& ?h, tap raw ofe

Xupp`dkdftory Jic& ?h, djt pofd`)& Kardavdr, ikkufamàttifc aj hdrdmd`òr sokp`ds sgawde

tgot tgd pratdif `dvd`s aj o`` tgrddGR? pratdif isajarks 'GR?ofe) wdrd sdvdrd`y

rdeuhde if LA ofiko`s hakporde ta haftra`s 'Xupp`dkdftory Jic& ?e)& Ugd rdprdssivd

gistafd G? o`sa eispòyde omdrroft stoififc ofe wos kard eijjusd ifM]HO? kutoft hartihds

'Xupp`dkdftory Jic& =o)& Atgdr prdviaus`y hgorohtdrizde rdprdssivd gistafds, suhg os KohraG=O? ofe gdtdrahgrakotif korldrs, suhg os gistafd G8 eikdtgy` @ys 9, eie fat oppdor ta md

ojjdhtde myM]HO? LA 'Xupp`dkdftory Jic& =m)& Xifhd wd govd prdviaus`y sgawf tgot tgd

M]HO? pratdif prdjdrdftio``y kafa+umiquitifotds gistafd G=O if vitra tgraucg its F+

tdrkifo` ]IFC jifcdr7, wd ifvdsticotde wgdtgdrM]HO? is ifva`vde if gdtdrahgrakotif

jarkotiaf tgraucg gistafd G=O umiquityòtiaf& Sd jaufe tgot tgd stoififc aj kafa+

umiquityòtde gistafd G=O, wgihg gos rdhdft`y mddf ikpìhotde ifpa`yhakm+kdeiotde

si`dfhifc9, harrdspafede ta tgd gdtdrahgrakotih hdftdrs edshrimde if Jic& ?m ofe tgot tgd

stoififc sicfo` wos rdeuhde ifM]HO? kutoft mroifs 'Jic&?h mattak raw ofe Xupp`dkdftory

Jic&?h ricgt pofd`)& Sd vdrijide tgd hd`` outafakaus foturd aj aur amsdrvotiafs usifc

hu`turde dkmryafih fduro` pracdfitar hd``s 'FRHs) if vitra& Udf eoys ojtdr fdurafo`

eijjdrdftiotiaf, tgdM]HO?+edjihidft hd``s eispòyde o sicfijihoft rdeuhtiaf if tgd fukmdr aj

gdtdrahgrakotih hdftdrs '3&74 jahi!hd`` vs 4&22 jahi!hd``, Xtuedfts t+tdst, p02&2224)

'Xupp`dkdftory Jic& =h)& Uoldf tacdtgdr, tgdsd eoto strafc`y succdst tgot hd``s òhlifcM]HO? ord ikpoirde if tgd arcofizotiaf aj gdtdrahgrakotif struhturd&

Gdtdrahgrakotih si`dfhifc eisruptiaf

Ua oshdrtoif tgot tgd amsdrvde gdtdrahgrakotih struhturo` edjihidfhids ord aj jufhtiafo`

ikpartofhd, wd ifvdsticotde tgd trofshriptiafo` stotus aj lfawf si`dfhde cdfds& Edjdhts ord

^gu dt o`& Rocd =

Foturd& Outgar kofushript< ovoiòm`d if RKH =2?= Korhg 7&

FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


3/14

dxpdhtde ta rdsu`t if edrdprdssiaf aj farko``y si`dfhde cdfds if gdtdrahgrakotih rdciafs?2&

Ugd kurifd pdrihdftrih gdtdrahgrakotif hafsists aj strdthgds aj gicg`y rdpdtitivd EFO

d`dkdfts, ifhùeifc tgd konar ofe kifar sotd`ìtd rdpdots, wgihg kold up ~8$ ofe ~2&54$

aj tgd kausd cdfakd rdspdhtivd`y??& _uoftitotivd ]U+RH] dxpdrikdfts sgawde tgot tgd

`dvd`s aj kifar ofe konar sotd`ìtd trofshripts wdrd d`dvotde ?2&=+jaè ofe =3&8+jaè,

rdspdhtivd`y, if tgdM]HO? kutoft hartihds, ifeihotifc o àss aj rdprdssiaf if hafstitutivd

gdtdrahgrakotif 'Jic& =o)& Atgdr iftdrspdrsde rdpdtitivd d`dkdfts suhg os IOR?, XIFD? ofe

tgd @? @IFD d`dkdft wdrd òrcd`y ufojjdhtde& Ugis djjdht wos hd`` outafakaus os it wosamsdrvde if vitra if hu`turde dkmryafih FRHs 'Xupp`dkdftory Jic& 8o)& Ugd edjdhts if

gdtdrahgrakotih rdprdssiaf ifM]HO?+edjihidft kausd hd``s hauè md rdvdrsde my rd+

dxprdssiaf aj gukofM]HO? usifc o dftiviro` vdhtar 'Jic& =m)& Gdtdrahgrakotif rdprdssiaf

myM]HO? is fat ufiqud ta fduro` hd``s mdhousd ed`dtiaf ajM]HO? if jimramòsts jrak R3

kausd rimhocds o`sa sgawde uprdcuòtiaf aj matg sotd`ìtd trofshripts 'Xupp`dkdftory Jic&

8m)& XifhdM]HO? is o tukar supprdssar if mrdost hofhdr wd fdxt cdfdrotde kihd gormarifc o

kokkory còfe spdhijih ed`dtiaf ajM]HO? ofe ofo`yzde tgd iftdcrity aj gdtdrahgrakotif

my q]U+RH] 'Jic& =h)& Ugd rdsu`t edkafstrotde tgot òhl ajM]HO? if kokkory còfes

jrak :+wddl aè vircif jdko`ds, eisruptde gdtdrahgrakotih sotd`ìtd EFO si`dfhifc os wd``

os ikpriftdeG?9 dpicdfdtih rdcuòtiaf, hafsistdft witg aur jifeifcs ifM]HO? fu`` mroifs

'Jic& =o)&

Ugd si`dfhifc aj hafstitutivd gdtdrahgrakotif my M]HO? is o`sa fat ìkitde ta kausd hd``s,os sotd`ìtd trofshripts jrak gukof Gd@o hd``s wdrd uprdcuòtde upaf dxprdssiaf aj of

sg]FO torcdtifcM]HO? 'Xupp`dkdftory Jic& 5o)& Xikiòr`y, rdhafstitutiaf aj tgd gukof

M]HO?+edjihidft hd`` ifd, GHH?983, witg o rdtravirus dxprdssifc wiètypdM]HO?

rdprdssde tgd dxprdssiaf aj sotd`ìtd EFO trofshripts omaut =2+jaè 'Jic& =e)& Ua edtdrkifd

wgdtgdr tgd F+tdrkifo` ]IFC eakoif aj M]HO? is ikpartoft jar tgd gdtdrahgrakotih

si`dfhifc jufhtiaf, wd rdhafstitutde GHH?983 hd``s witg ditgdr o potgacdfihM]HO? kutoft

edvaie aj umiquitif ìcosd ohtivity 'U83], lfawf ta hafjdr ifhrdosde hofhdr risl) ar o

pa`ykarpgih vorioft 'Z??O, ifeistifcuisgom`d jrak wiètypd)& Ugd U83] kutoftM]HO?

joi`de ta rdprdss sotd`ìtd trofshripts wgdrdos tgd Z??O rdprdssde tgd sotd`ìtd trofshripts ta

of dxtdft sikiòr ta wiètypdM]HO? 'Jic& =e)& Ugd òhl aj rdprdssivd ohtivity wos fat eud ta

rdeuhde mifeifc aj MO]E?, tgd foturo` gdtdraeikdrih portfdr aj M]HO?, os matg

pa`ykarpgih ofe kutoft ikkufaprdhipitotdeMO]E? sikiòr`y 'Xupp`dkdftory Jic& 5m)& Ua

jurtgdr vdrijy tgd ifva`vdkdft aj tgd D8+ìcosd ohtivity ajM]HO?, wd ossdssde tgd djjdhts ajMO]E? lfahleawf af sotd`ìtd EFO trofshriptiaf sifhd tgd gdtdraeikdrizotiaf mdtwddf

M]HO? ofeMO]E? is rdquirde jar tgd aptiko` D8 ìcosd ohtivity7,?=& Dxprdssiaf aj of

sg]FO ocoifstMO]E? d`dvotde tgd sotd`ìtd EFO trofshriptiaf if tgdM]HO? rdhafstitutde

GHH?983 hd``s mut fat if tgd GHH?983 hd``s wgdrdM]HO? is omsdft ofe tgd sotd`ìtd rdpdot

trofshriptiaf is o`rdoey edrdprdssde 'Xupp`dkdftory Jic& 5h)& Ugdsd rdsu`ts jrak hu`turde

gukof hd``s ord hafsistdft witg eoto amtoifde jrak tgd M]HO? edjihidft kausd mroifs,

jimramòsts ofe kokkory còfes if wgihg sotd`ìtd EFO trofshript ifeuhtiaf wos amsdrvde&

Kardavdr, it oppdors tgot umiquitif D8 ìcosd ohtivity ajM]HO? is dssdftio` jar its ra`d if

cdfd si`dfhifc if hafstitutivd gdtdrahgrakotif&

M]HO? ofe gdtdrahgrakotif rdòtiafsgip

Ua coif o kdhgofistih ifsicgt ifta tgd ra`d aj M]HO? if koiftoififc gdtdrahgrakotifstruhturd, wd jirst ifvdsticotde ijM]HO? eirdht`y ossahiotds witg tgd hafstitutivd

gdtdrahgrakotih rdciaf if viva& Hgrakotif ikkufaprdhipitotiaf 'HgIR) dxpdrikdfts sgawde

tgotM]HO? wos ifedde dfrihgde af konar ofe kifar sotd`ìtd EFO 'Jic& =d) if kausd hd``s

ofe af voriaus sotd`ìtd sdqudfhds if Gd@o hd``s 'Xupp`dkdftory Jic& 5e)&

^gu dt o`& Rocd 8


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


4/14

Sd fdxt tdstde wgdtgdrM]HO? ifjùdfhde gistafd umiquityòtiaf if viva& Ugd rdsu`ts aj

HgIR dxpdrikdfts sgawde tgot umiquityòtde gistafd G=O wos dfrihgde if matg konar ofe

kifar sotd`ìtd rdciafs wgdf hakporde witg o gistafd G8 oftimaey 'Jic& =j)& Gawdvdr, tgis

sotd`ìtd rdciaf dfrihgkdft wos omracotde if tgd omsdfhd ajM]HO?, ifeihotifc tgotM]HO?

iftdcrity is dssdftio` jar tgd ohhukuòtiaf aj umiquity`+gistafd G=O ot sotd`ìtd rdpdots if

viva& Aur eoto o`sa sgaw tgot umiquity`+gistafd G=O is dfrihgde ot tgd sotd`ìtd rdciafs aj tgd

kausd cdfakd ta o crdotdr dxtdft tgof ot atgdr iftdrspdrsde rdpdots suhg os @IFD? 'eoto fat

sgawf) succdstivd aj o eistifht gdtdrahgrakotif& IjM]HO? is ifedde tgd umiquitif ìcosd jarpdrihdftrih gdtdrahgrakotih gistafd G=O, it wauè ikp`y tgot tgd iftdcrity aj tgd ]IFC

jifcdr is rdquirde jar tgd ohhukuòtiaf aj umiquityòtde gistafd G=O ot sotd`ìtd rdpdots, os

wd govd sgawf tgot tgd sokd rdciaf is hritiho` jar trofshriptiafo` si`dfhifc if tgd

gdtdrahgrakotif 'Jic& =e)& Ua tdst tgis gypatgdsis, HgIR dxpdrikdfts wdrd pdrjarkde usifc

GHH?983 hd``s rdhafstitutde witgM]HO?+U83],M]HO?+Z??O, arCJR 'Jic& =c)& Ugd

U83] kutoftM]HO? joi`de ta sicfijihoft`y dfrihg umiquityòtde gistafd G=O ot sotd`ìtd

rdciafs, if o koffdr sikiòr ta CJR haftra`, wgi`d tgd pa`ykarpgihM]HO?+Z??O sgawde

dfrihgkdft aj umiquityòtde gistafd G=O witgif tgd sokd rdciafs& O eistifht kutoft I=:O

wgihg gos mddf rdpartde ta fat edstomiìzd tgdMO]E? iftdrohtiaf mut gos fa umiquity` ìcosd

ohtivity?8 joi`s ta hakp`dkdft tgd àss ajM]HO? 'Xupp`dkdftory Jic& 4)& Ugd umiquity`

ìcosd jufhtiaf ajM]HO? oppdors ta md spdhijih os ed`dtiaf aj]ifc?M ar lfahleawf aj

]FJ7joi` ta opprdhiom`y edrdprdss sotd`ìtd trofshriptiaf 'Xupp`dkdftory Jic& :)& Ugdsd

jifeifcs pravied jurtgdr dviedfhd tgot tgdM]HO? umiquitif ìcosd ohtivity is dssdftio` jar tgdkoiftdfofhd aj tgd umiquity` gistafd G=O korl witgif hafstitutivd gdtdrahgrakotih rdciafs

fat af`y if kausd tissud mut o`sa gukof hd``s edrivde jrak mrdost hofhdrs&

Tmiquityòtde gistafd G=O rdshuds M]HO?

Ua ossdss tgd haftrimutiaf aj umiquity`+gistafd G=O ta tgd jufhtiaf ajM]HO? if

gdtdrahgrakotih si`dfhifc wd cdfdrotde o dftiviro` vdhtar hafstruht dxprdssifc of G=O+Tm

jusiaf pratdif tgot kikihs tgd foturo` umiquity` gistafd G=O 'Jic& 8o)& Ugis wos

ohhakpìsgde my jusifc o sifc`d umiquitif kaidty ta tgd H+tdrkifus aj gistafd G=O if ìdu

aj tgd kaeijihotiaf aj `ysifd ??9& Xumfuh`dor jrohtiafotiaf aj hd``s dxprdssifc tgis jusiaf

pratdif sgaws tgot tgd G=O+Tm pratdif ofe kutofts hof md ifharparotde ifta hd` uòr

hgrakotif 'Xupp`dkdftory Jic& 3)&M]HO? edjihidft GHH?983 hd``s wdrd trofseuhde witg

`dftivirus dxprdssifc tgd G=O+Tm jusiaf pratdif& _uoftijihotiaf aj tgd dvd`s aj sotd`ìtdEFO trofshriptiaf sgawde tgot tgd G=O+Tm dxprdssiaf hof rd+dstomìsg si`dfhifc aj tgd

sotd`ìtd rdpdots 'khMax, XOUo ofe XOUIII) witgif gdtdrahgrakotif ifM]HO?+edjihidft

gukof hd``s, succdstifc tgot kafa+umiquity`+G=O is ìld`y ta md tgd koif torcdt ajM]HO?

umiquitif D8 icosd tgot kdeiotds si`dfhifc ot hafstitutivd gdtdrahgrakotif 'Jic& 8m)& Dhtapih

dxprdssiaf aj G=O+Tm 'Xupp`dkdftory Jic& 7) if kurifd FRHs rdstarde tgd `dvd`s aj

sotd`ìtd EFO si`dfhifc ta kard tgof 92$ aj dfeacdfaus wiètypd si`dfhifc 'Jic& 8h)&

Kutotiafs witgif tgd umiquitif eakoif aj tgd jusiaf pratdif rdeuhde tgd omiìty ta rdstard

si`dfhifc aj tgd G=O+Tm jusiaf pratdif 'Xupp`dkdftory Jic& 9o)& G=O+Tm dxprdssiaf if

wiè typd hd``s goe fa sicfijihoft djjdht af tgd sotd`ìtd EFO trofshriptiaf& Ua ifquird

wgdtgdr tgd umiquityòtiaf aj gistafd G=O ojjdhtde prdviaus`y wd``+eahukdftdeM]HO?

jufhtiafs, wd tdstde ij tgd rdstarde sotd`ìtd EFO si`dfhifc ifM]HO? fu`` hd``s goe ofy aj

tgd dxpdhtde hafsdqudfhds& It gos mddf rdpartde tgot prikoryM]HO? fu`` hd``s eispòy o

sdvdrd crawtg edjdht ofep48+ohtivotde opaptasis ofe tgotp48 ifohtivotiaf orcd`y rdshudstgd crawtg edjdht?5& My pdrjarkifc MreT ifharparotiaf ossoys, wd jaufe tgot dhtapih

dxprdssiaf aj G=O+Tm `de ta o rdstarotiaf aj avdr 34$ aj praìjdrotiaf ifM]HO? edjihidft

hd``s, af`y sìcgt`y àwdr tgof op48 lfahleawf 'Jic& 8e)& Ocoif, if tgis hosd dxprdssiaf aj

G=O+Tm mypossde tgd rdquirdkdft jarM]HO?& It is wartgy ta fatd tgot o`tgaucgp48 is om`d

ta rdshud tgd praìjdrotivd edjdht ajM]HO? edjihidft hd``s, it eads fat rdshud tgd jarkotiaf

aj gdtdrahgrakotih hdftdrs, ar tgd edrdprdssiaf aj sotd`ìtd trofshripts 'Xupp`dkdftory Jic&

^gu dt o`& Rocd 5


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


5/14

?2)& Sd o`sa dvoùotde tgd omiìty aj G=O+Tm ta supprdss opaptasis& Xtoififc jar of

opaptatih korldr, ohtivd hosposd8, sgawde o sikiòr rdsu`t 'Jic& 8d) ta wgot wos sddf jar

MreT ifharparotiaf ar trofshriptiafo` si`dfhifc& Ugus G=O+Tm hof supprdss tgd opaptasis

ifeuhde my tgd àss ajM]HO?& Uoldf tacdtgdr, dhtapih dxprdssiaf aj G=O+Tm fat af`y

rdstarde si`dfhifc mut o`sa rdshude tgd praìjdrotivd edjdht ofe opaptasis ajM]HO? edjihidft

hd``s& Ugis rdshud aj tgd praìjdrotivd hopohity aj G=O+Tm is spdhijih jar tgd umiquityòtiaf

kaeijihotiaf, os kutotiafs witgif tgd umiquitif eakoif hof omracotd tgd djjdht

'Xupp`dkdftory Jics& 9m ofe 9h)& Gakaàcaus rdhakmifotiaf, ofatgdr rdpartde hd`ùòrprahdss if wgihgM]HO? gos mddf ikpìhotde, hof o`sa md rdshude my dhtapih G=O+Tm

dxprdssiaf if tgd omsdfhd ajM]HO?, wgdrdos tgd sokd pratdif witg o trip`d paift kutotiaf

witgif tgd umiquitif eakoif is ufom`d ta hakp`dkdft 'Xupp`dkdftory Jic& ??)& Ugus, kafa+

umiquity`+G=O is ìld`y tgd prifhipo` torcdt ajM]HO? jar koiftoififc gdtdrahgrakotif

iftdcrity if viva&

Gdtdrahgrakotif ofe M]HO? tukar supprdssiaf

Sd fdxt ifvdsticotde tgd sicfijihofhd aj gdtdrahgrakotif jufhtiaf ifM]HO? kdeiotde

tukar supprdssiaf& Kausd mrdost tukars 'Jic& 5o) wdrd gorvdstde jrak ofiko`s wgdrd

M]HO? wos ed`dtde if tgd kokkory còfe 'o`sa sgawf if Jic& =h)& Ofo`ysds my q]U+RH]

sgawde eisruptde sotd`ìtd EFO si`dfhifc ifM]HO? edjihidft kausd kokkory tukars, mut

fat if tissuds wgdrdM]HO? is iftoht 'Jic& 5m)& Jurtgdrkard, wd ofo`yzde sotd`ìtd trofshriptsif gukof mrdost tukars edrivde jrak dicgt ifeivieuo`M]HO? kutotiaf horridrs ofe jaufe

sicfijihoft edrdprdssiaf aj tgd dxprdssiaf aj o`pgo sotd`ìtd rdpdots> HJWr ofe XOUo 'twa aj

gukof o`pgo sotd`ìtd EFO sdqudfhds< Jic& 5h)& Ugd eijjdrdfhds ord oppordft, dvdf witgaut

farkoìzifc jar ofy atgdr johtars 'd&c& tgd pdrhdftocd aj faf+tukar hd`` haftokifotiaf), if

hakporisaf witg o hagart aj farko` mrdost miapsids&

Xotd`ìtd trofshript ifeuhde cdfakih ifstomiìty

Ua ifvdsticotd wgdtgdr tgd amsdrvde sotd`ìtd EFO edrdprdssiaf if kausd ofe gukof mrdost

hofhdrs is ditgdr of dpipgdfakdfaf ar aj dtiaàciho` sicfijihofhd jar tgd cdfdsis aj hofhdr,

wd dhtapiho``y dxprdssde sotd`ìtd EFO jrak o trofseuhde `dftiviro` vdhtar 'Jic& 4o) if

hu`turde prikory gukof kokkory dpitgdìo` hd``s 'GKDHs)& Ugdsd hd``s ifhrdosde

omfarko` kitatih jicurds, ifhùeifc mriecde ofe òccifc hgrakasakds ofe eisarcofizdekdtopgosds sgawf my EORI stoififc 'Jics& 4m ofe supp`dkdftory Jic&?=)&

Ikkufajùardshdfhd stoififc aj pdrihdftrif ofe tumuìf rdvdo`de okpìjide hdftrasakds, os

prdviaus`y edshrimde ifM]HO? fu`` hd``s 'Jic& 4h)& Hd``s avdrdxprdssifc sotd`ìtd ]FO o`sa

eispòyde fukdraus jahi ajG=Ox 'Jic& 4e), o wd``+dstomìsgde korldr aj EFO eaum`d

strofe mrdols& Ugis kirrars tgd pgdfatypd ajM]HO? edjihidft hd``s& Jàw hytakdtrih

ofo`ysds sgawde of ikpoirde kitatih spife`d hgdhlpaift wgdf hd``s avdrdxprdssifc sotd`ìtd

EFO wdrd trdotde witg fahaeoza`d 'Jic& 4d), wgihg gos o`sa mddf rdpartde os oM]HO? àss

pgdfatypd?4& Nust os dxpdhtde, dhtapih dxprdssiaf aj sotd`ìtd ]FO wos om`d ta hrdotd o

edjihidfhy if gakaàcaus rdhakmifotiaf sikiòr if kocfitued ta tgd lfahleawf ajM]HO?

'Xupp`dkdftory Jic&?8)& Ikpartoft y, tgd hd`ùòr edjdhts ossahiotde witg sotd`ìtd ]FO

avdrdxprdssiaf ord cdfdro``y hafsiedrde doeifc housds jar cdfakih ifstomiìty&

Eishussiaf

Ugd prdsdft warl sgaws tgotM]HO? edjihidfhy ikpoirs tgd iftdcrity aj hafstitutivd

gdtdrahgrakotif wgihg `does ta tgd eisruptiaf aj cdfd si`dfhifc ot tgd tofedk`y rdpdotde

EFO rdciafs, pramom`y tgraucg tgd àss aj umiquitifotiaf aj gistafd G=O&M]HO?!MO]E?

pratdifs prdjdrdftio``y kafa+umiquityòtd G=O ot gicg staihgiakdtry7, wgihg hakprisds

4+?4$ aj tgd tato` hd`ùòr fuh`dasako` gistafd G=O?:& M]HO? ohhukuòtds G=O+Tm ot

^gu dt o`& Rocd 4


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


6/14

sotd`ìtd EFO rdciafs, wgihg dfhakposs ~8&54$ aj tgd kausd cdfakd?? 'Jic& =j) ofe itsd`j

àhoìzds tgdrd my HgIR dxpdrikdfts 'Jic& =d)& UgdM]HO? ]IFC eakoif is dssdftio` jar

matg sotd`ìtd EFO mifeifc ofe si`dfhifc&MO]E? is o`sa rdquirde jar rdprdssiaf aj sotd`ìtd

rdpdots ofe àss ajMO]E? is aj fa hafsdqudfhd ijM]HO? is o`rdoey omsdft 'Xupp`dkdftory

Jic& 5h)& O`tgaucg tgd dxoht jufhtiaf is fat wd`` ufedrstaae, tgd dkdrcifc fatiaf is tgot

kafa+umiquitifotde gistafd G=O is kast jrdqudft`y ossahiotde witg trofshriptiafo` y

rdprdssivd stotds9,?3,?7& Atgdr umiquity` icosds>]ifc?O!M, aj tgd pa`yhakm rdprdssivd

hakp`dx ? 'R]H?), ofe]FJ7 o EFO rdpoir ìcosd?9,=2

umiquityòtd G=O mut ea fathaftrimutd ta tgd si`dfhifc aj sotd`ìtd rdpdots 'Xupp`dkdftory Jic& :)& Xikiòr`y,MOR?, o

lfawf M]HO? mifeifc pratdif, gos mddf sgawf ta oftocafizd tgd pa`yhakm hakp`dx my

edumiquitifotifc gistafd G=O=?,==& Xifhd o kikih aj foturo` umiquity`+G=O hof rdshud tgd

kast prakifdftM]HO? edjihidfhy edjdhts, it succdsts tgot umiquityòtiaf aj gistafd G=O is

ìld`y ta md tgd prikory sumstrotd ajM]HO? 'Jics& 8 ofe Xupp`dkdftory Jic& 9)&

It is wartg fatifc tgot avdrdxprdssiaf aj tgd sotd`ìtd trofshripts if tgd prdsdfhd aj wiètypd

M]HO? portio``y pgdfahapidsM]HO? àss 'Jic& 4), ifhùeifc hdftrasakd okpìjihotiaf ofe

G=Ox jahi jarkotiaf& Ugdsd amsdrvotiafs succdst hafstitutivd gdtdrahgrakotif jarkotiaf

prdvdfts EFO eokocd ar o EFO eokocd rdspafsd& Ugd jufhtiaf aj sotd`ìtd trofshripts is

òrcd`y uflfawf& Gawdvdr, it gos mddf lfawf tgot tgd iftdcrity aj hdftrakdrih

gdtdrahgrakotif rdquirds of uflfawf ]FO hakpafdft3 tgot hauè hafhdivom`y md sotd`ìtd

trofshripts&

Uukar supprdssiaf myM]HO? wos prdsukde ta ahhur vio gakaàcaus rdhakmifotiaf8&

]dhdft warl sgawde tgot hd``s dxprdssifc o kutoftM]HO? edvaie aj D8 ìcosd ohtivity ea

fat dxgimit edjdhts if gakaàcaus rdhakmifotiaf?8& Ugus, tgd edjdht if cdfakih ifstomiìty

ifM]HO? fu`` hd``s sddks fat ta rdquird tgis jufhtiaf o`tgaucg of iftoht ]IFC eakoif is

rdquirde jar rdhavdry jrak cokko irroeiotiaf=8& Fdvdrtgd`dss, kutotiafs tgot hakprakisd

tgd umiquity` ìcosd ohtivity ajM]HO? ord hofhdr prdeispasifc ofe hafstitutd gatspats aj

kutotiafo` ahhurrdfhds if potidfts=8& Aur warl sgaws tgot sotd`ìtd EFO rdprdssiaf ifedde

rdquirds of iftohtM]HO? ]IFC eakoif, hafsistdft witg sotd`ìtd EFO edrdprdssiaf

amsdrvde ifM]HO? tukars 'Jic& =e)& Ifedde sotd`ìtd trofshripts if hìfiho` M]HO? potidft

tukars ord uprdcuòtde 'Jic& 5h)& Xifhd sotd`ìtd trofshripts wgdf dxprdssde dhtapiho``y hof

ifeuhd hdftrasakd okpìjihotiaf, hd`` hyh`d hgdhl paift edjdht ofe tgd EFO eokocd

rdspafsd, it ju`ji``s tgd hritdrio ta md o koif djjdhtar ajM]HO? kdeiotde tukaricdfdsis&O`tgaucg it is prdsdft`y ufh`dor gaw tgdsd prahdssds ord dìhitde ot o kdhgofistih `dvd` it is

tdkptifc ta spdhuòtd tgot gistafd G=O umiquityòtiaf potgwoys ord ifva`vde& O`tdrfotivd`y,

tgd edrdprdssiaf aj sotd`ìtd kicgt md dìhitde my sakd ifeirdht càmo` djjdht if trofs tgot

wauè fat rdquird G=O+Tm ta md ot tgd edrdprdssde sitd& It is hafhdivom`d tgot ifeuhtiaf aj

sotd`ìtd trofshripts hauè md edvdàpde ifta o korldr aj àss aj gdtdrazycasity jar hìfiho`

eiocfastih oppìhotiaf& ]dhdft warl gos sgawf tgot o voridty aj dpitgdìo` hofhdrs

avdrdxprdss sotd`ìtd rdpdots tgot dfhakposs up ta 42$ aj hd`ùòr trofshripts=5& O`tgaucg

tgd potgaàciho` sicfijihofhd aj tgis jifeifc is uflfawf, aur warl succdsts tgot tgdsd hauè

haftrimutd ta tgd dvaùtiaf aj tgd hofhdr hd`` tgraucg tgd ifeuhtiaf aj cdfakih ifstomiìty

'Xupp`dkdftory Jic& ?5)&

Kdtgaes Xukkory

Hd`` hu`turd, virus ifjdhtiaf, quoftitotivd ]U+RH] ofe HgIR dxpdrikdfts& Rrikory fduro`

pracdfitar hd``s wdrd isaòtde jrak oeu`t kihd haftoififc afdM]HO? fu`` o``d`d ofe afd

jàxdeM]HO? o``d`d os edshrimde=4& Dkmryafih fduro` pracdfitars wdrd isaòtde ofe

hu`turde os edshrimde=:& Hu`turde hd``s wdrd ifjdhtde witg rdtravirusds witg of KAI aj 4 jar

?=+g ofe gorvdstde ot tgd tikd ifeihotde if harrdspafeifc jicurd `dcdfes& Hd``s wdrd

gorvdstde witg U]IÂ@ jar ]FO dxtrohtiaf& ]dvdrsd trofshriptiaf wos horride aut usifc

^gu dt o`& Rocd :


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


7/14

XupdrXhript III Jirst+strofe Xyftgdsis Xystdk 'Ifvitracdf)& Ugd quoftitotiaf aj RH] praeuhts

wos ofo`yzde witg XYM] Crddf usifc OMI R]IXK 3322 Xdqudfhd Edtdhtiaf systdk

sajtword 'Oppìde Miasystdks)& Hrassìflifc ofe HgIR wdrd pdrjarkde os o kaeijide

vdrsiaf aj o prataha` edshrimde my tgd H`dvdrs òmarotary=3 ofe supp`dkdftory ifjarkotiaf&

Ju`` Kdtgaes ofe ofy ossahiotde rdjdrdfhds ord ovoiòm`d if tgd afìfd vdrsiaf aj tgd popdr

ot www&foturd&hak!foturd&

Xupp`dkdftory Kotdrio`

]djdr ta Sdm vdrsiaf af RumKde Hdftro` jar supp`dkdftory kotdrio`&

Ohlfaw`deckdfts

Ugd outgars tgofl Mormoro Ki``dr jar ossistofhd if hu`turifc FRH, Ducdfd Ld jar eishussiaf ofe ofo`ysis aj

Ojjykdtrix eoto, Er& Okid` Yofoi jar tgd M]HO? torcdtifc sg]FO hafstruht, Er& Horaìfd @i``dy jar ossistofhd

witg Sdstdrf màttifc, ofe Er& ^gafcsgdfc Yau jar ossistofhd witg tgd @I+HA] Aeyssdy Ifjrorde Ikocifc Xystdk&

Sd tgofl Er& Oftaf Mdrfs jar gis sustoifde iftdrdst if tgis warl ofe pravieifc kutoft kihd ofe kotdrio`s ofe Er&

Kicud` Zieo` jar pravieifc kausd dkmrya jimramòsts haftoififc hafeitiafo` ed`dt iaf o``d`d aj ]ifc ?M& _^ wos

suppartde my tgd Hoìjarfio Mrdost Hofhdr ]dsdorhg Rracrok ofe ]utg @& Lirshgtdif Fotiafo` ]dsdorhg Xdrvihd

Owore& CKR wos suppartde my o jd`àwsgip aj tgd Hoìjarfio Ifstitutd aj ]dcdfdrotivd Kdeihifd& GX is o rdhipidft

aj OXRDU+Kdrhl jd`àwsgip& IKZ is of Okdrihof Hofhdr Xahidty Rrajdssar aj Ka`dhuòr Miaàcy, ofe gaès tgd

Irwif ofe Naof Nohams Hgoir if Dxdkpòry @ijd Xhidfhd& Ugis warl wos suppartde if port my crofts jrak tgd FIG,Ipsdf!Miakdosurd, Xofaji Ovdftis, ofe tgd G&F& ofe Jrofhds H& Mdrcdr Jaufeotiaf& JGC is suppartde my FIG

FX4=75=, FX42=?3, ofe tgd @aalaut Jufe&

]djdrdfhds

?& Uutt O, Osgwartg O& Ugd rdòtiafsgip mdtwddf tgd ra`ds aj M]HO? cdfds if EFO rdpoir ofe hofhdr

prdeispasitiaf& Urdfes if Ka`dh Kde& =22=< 7>43?43:& \RumKde> ?=532992[

=& Lifc KH, Korls NG, Kofed`` NM& Mrdost ofe avoriof hofhdr risls eud ta ifgdritde kutotiafs if

M]HO? ofe M]HO=& Xhidfhd& =228< 82='4:54)>:58:5:& \RumKde> ?543:585[

8& Gudf KX, Xy XK, Hgdf N& M]HO? ofe its taa`max jar tgd koiftdfofhd aj cdfakd iftdcrity& Fot

]dv Ka` Hd`` Mia`& =2?2< ??'=)>?87?57& \RumKde> =22=95=2[

5& Rocdou CN, Go`` @@, Cofdsof X, @ivifcstaf EK, @owrdfhd NM& Ugd eisoppdorifc Morr maey if

mrdost ofe avoriof hofhdrs& Fot ]dv Hofhdr& =223< 3'7)>:=7:88& \RumKde> ?3:??454[

4& @ofd UJ, dt o`& Dxprdssiaf aj Mrho? is ossahiotde witg tdrkifo` eijjdrdftiotiaf aj dhtaedrko``y ofe

kdsaedrko``y edrivde tissuds if kihd& Cdfds Edv& ?994< 9>=3?==3==& \RumKde> 3492=53[

:& Largafdf @, Mroffvo`` L, Xlacàso Y, @ifega`k E& Uukar supprdssar cdfd M]HO+? is dxprdssde

my dkmryafih ofe oeu`t fduro` stdk hd``s ofe ifva`vde if hd`` praìjdrotiaf& N Fdurashi ]ds& =228=9:825& \RumKde> ?423?445[

7& Wio Y, Roa CK, Hgdf GS, Zdrko IK, Guftdr U& Dfgofhdkdft aj M]HO? D8 umiquitif ìcosd

ohtivity tgraucg eirdht iftdrohtiaf witg tgd MO]E? pratdif& N Mia` Hgdk& =228< =37'3)>4=444=:8&

\RumKde> ?=58?99:[

9& Sofc G, dt o`& ]a`d aj gistafd G=O umiquitifotiaf if Ra`yhakm si`dfhifc& Foturd& =225< 58?'32?2)>

738737& \RumKde> ?487:2==[

?2& Kdfdcgifi KE, Su K, Koegofi GE& Hafsdrvde gistafd vorioft G=O&^ pratdhts duhgrakotif

jrak tgd dhtapih sprdoe aj si`dft gdtdrahgrakotif& Hd``& =228< ??='4)>3=438:& \RumKde>

?=:=7?9?[

??& Kortdfs NG, dt o`& Ugd praji`d aj rdpdot+ossahiotde gistafd `ysifd kdtgyòtiaf stotds if tgd kausd

dpicdfakd& Dkma N& =224< =5'5)>7227?=& \RumKde> ?4:37?25[

?=& Gosgizukd ], dt o`& Ugd ]IFC gdtdraeikdr M]HO?+MO]E? is o umiquitif ìcosd ifohtivotde my o

mrdost hofhdr+edrivde kutotiaf& N Mia` Hgdk& =22?< =3:>?5483?5452& \RumKde> ??=37=53[

^gu dt o`& Rocd 3


FIG+ROO

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FIG+ROOutgar

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http://www.nature.com/nature


8/14

?8& ]die @N, dt o`& D8 ìcosd ohtivity aj M]HO? is fat dssdftio` jar kokkoìof hd`` viomiìty ar

gakaàcy+eirdhtde rdpoir aj eaum`d+strofe EFO mrdols& Rrah Fot` Ohoe Xhi T X O& =227=::=3?& \RumKde> ??58?:97[

?4& Xoflorof X, Xtorito @K, Cradf OH, La KN, Rorvif NE& Hdftrasako` kihratumu`d fuh`dotiaf

ohtivity is ifgimitde my M]HO?+edpdfedft umiquitifotiaf& Ka` Hd`` Mia`& =224< =4'?9)>7:4:7::7&

\RumKde> ?:?:::54[

?:& Kotsui XI, Xdaf ML, Xofemdrc OO& Eisoppdorofhd aj o struhturo` hgrakotif pratdif O=5 if

kitasis> ikpìhotiafs jar ka`dhuòr mosis aj hgrakotif hafedfsotiaf& Rrah Fot` Ohoe Xhi T X O&

?939< 3:'?=)>:87::892& \RumKde> =983=3[

?3& Lo`ìf DK, dt o`& Cdfakd+wied uG=O ahoìzotiaf ofo`ysis gicgìcgts Mki?+edpdfedft edpasitiaf

aj tgd korl ot rdprdssde cdfds& R@aX Cdfdt& =229< 4':)>d?22242:& \RumKde> ?9428494[

?7& ^gau S, dt o`& Gistafd G=O kafaumiquitifotiaf rdprdssds trofshriptiaf my ifgimitifc ]FO

pa`ykdrosd II trofshriptiafo` dàfcotiaf& Ka` Hd``& =227< =9'?)>:972& \RumKde> ?7=2:932[

?9& Eai` H, dt o`& ]FJ?:7 mifes ofe okpìjids umiquitif hafnucotds af eokocde hgrakasakds ta o`àw

ohhukuòtiaf aj rdpoir pratdifs& Hd``& =229< ?8:'8)>58455:& \RumKde> ?9=28439[

=2& Xtdwort CX, dt o`& Ugd ]IEE@D syferakd pratdif kdeiotds o umiquitif+edpdfedft sicfoìfc

hoshoed ot sitds aj EFO eokocd& Hd``& =229< ?8:'8)>5=2585& \RumKde> ?9=28437[

=?& Xhgdudrkoff NH, dt o`& Gistafd G=O edumiquitifosd ohtivity aj tgd Ra`yhakm rdprdssivd hakp`dx

R]+ETM& Foturd& =2?2< 5:4'3=94)>=58=53& \RumKde> =258:549[==& Ndfsdf ED, dt o`& MOR?> o favd` umiquitif gyeraòsd wgihg mifes ta tgd M]HO? ]IFC jifcdr ofe

dfgofhds M]HO?+kdeiotde hd`` crawtg supprdssiaf& Afhacdfd& ?997< ?:'9)>?293???=&

\RumKde> 94=774=[

=8& ]ujjfdr G, Naozdira HOR, Gdkkoti E, Guftdr U, Zdrko IK& Hofhdr+prdeispasifc kutotiafs

witgif tgd ]IFC eakoif aj M]HO?> @ass aj umiquitif pratdif ìcosd ohtivity ofe pratdhtiaf jrak

roeiotiaf gypdrsdfsitivity& Rrah Fot` Ohoe Xhi 'TXO)& =22?< 97'9)>4?854?89& \RumKde>

??8=2=42[

=5& Uifc EU, dt o`& Omdrroft avdrdxprdssiaf aj sotd`ìtd rdpdots if pofhrdotih ofe atgdr dpitgdìo`

hofhdrs& Xhidfhd& =2??< 88?':2?3)>49849:& \RumKde> =?=88857[

=4& Ro`kdr UE, Korlolis DO, Si``gaitd O], Xojor J, Cocd JG& Jimramòst crawtg johtar+= ohtivotds o

òtdft fduracdfih pracrok if fduro` stdk hd``s jrak eivdrsd rdciafs aj tgd oeu`t HFX& N Fdurashi&

?999< ?9'?9)>75737593& \RumKde> ?2598359[

=:& Folosgiko L, dt o`& Xyfdrcistih sicfoìfc if jdto` mroif my XUOU8+Xkoe? hakp`dx mriecde myp822& Xhidfhd& ?999< =75'45?8)>53957=& \RumKde> ?2=24245[

=3& vof Ds NG, dt o`& Sft sicfo`ìfc ifeuhds koturotiaf aj Rofdtg hd``s if iftdstifo` hrypts& Fot Hd``

Mia`& =224< 3'5)>87?87:& \RumKde> ?433732:[

^gu dt o`& Rocd 7


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


9/14

Jicurd ?& M]HO? edjihidfhy ikpoirs gdtdrahgrakotif struhturd

o, Dxprdssiaf aj M]HO? is eikifisgde if tgdFdstif+HrdM]HO? lfahlaut mroifs os sgawf

my ikkufam`attifc& LA> sokp ds jrak o R3M]HO? LA 'Mrho??,!+


10/14

Jicurd =& M]HO? ofe its umiquitif D8 ìcosd ohtivity ord rdquirde jar cdfd si`dfhifc ifhafstitutivd gdtdrahgrakotif

o, _uoftitotivd ]U+RH] sgawde tgot gdtdrahgrakotih rdciafs ar hdrtoif ikpriftde cdfds

'Icj= *G?9 mut fatIcj=]) wdrd uprdcuòtde ifM]HO? LA mroifs& Iftdrfo` haftra`s>

hyhàpgiìf ar?7X]FO& m, ]dshud aj tgdM]HO? kdeiotde rdprdssiaf if FRHs my dxacdfaus

gukofM]HO? mut fat CJR ojtdr ifjdhtiaf witg rdtraviro` H]D+CJR& h, _uoftitotivd ]U+

RH] dxpdrikdfts sgawde tgot gdtdrahgrakotih rdciafs ar ikpriftde cdfds wdrd uprdcuòtdeif M]HO? LA kokkory còfes ':+wddl vircif)& e, Ugd umiquitif D8 ìcosd ohtivity aj

M]HO? is rdquirde jar gdtdrahgrakotif si`dfhifc& GHH?983 hd``s wdrd rdhafstitutde witg

ditgdr wiè typdM]HO? 'GHHM?) ar M]HO? witg o kutotiaf if tgd ]IFC eakoif, U83]=8&

R3 hdrdmd`òr HgIR dxpdrikdfts witg oftimaeids ocoifst 'd) kausdM]HO? arZXZC pratdif

os o haftra` ofe 'j) umiquity`+gistafd G=O ar gistafd G8 pratdif os o haftra`& Dfrihgkdft aj

konar ofe kifar sotd`ìtd EFO wos kdosurde my quoftitotivd RH] rdòtivd ta ?7X haftra`& c,

^gu dt o`& Rocd ?2


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


11/14

HgIR dxpdrikdfts wdrd pdrjarkde usifc umiquitifotde gistafd G=O oftimaey os if 'j) ofe

GHH?983 hd``s rdhafstitutde witg CJR,M]HO? 'Z??O) ar o kutoft 'U83])& Drrar mors ord

sgawf os s&e& Dohg rdsu`t sgawf is rdprdsdftotivd aj tgrdd ifedpdfedft dxpdrikdfts&

^gu dt o`& Rocd ??


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


12/14

Jicurd 8& Tmiquitifotde gistafd G=O is eirdht`y ifva`vde if M]HO? kdeiotde gdtdrahgrakotihsi`dfhifc

o, O eiocrok sgawifc tgd ortijihio` umiquitif+G=O dxprdssiaf vdhtar& m, GHH?983 hd``s

wdrd ifjdhtde witg o `dftiviro` vdhtar dxprdssifc umiquityòtde gistafd G=O kikih jusiaf

pratdif arCJR os o haftra` ofe tgd `dvd`s aj o`pgo sotd`ìtd voriofts 'khMax, XOUo ofe

XOUIII) trofshriptiaf wdrd kdosurde my q]U+RH]& h, Dhtapih dxprdssiaf aj umiquityòtde

gistafd G=O rd+dstomìsgde gdtdrahgrakotif si`dfhifc ifM]HO? fu`` FRHs& FRHs wdrd

ifjdhtde witg CJR oàfd, umG=O, H]D+CJR oàfd ofeH]D+CJR haifjdhtde witg TmG=O&

Ugd dvd`s aj sotd`ìtd EFO trofshriptiaf wdrd kdosurde my q]U+RH]& e, FRHs sgawde

ifhrdosde praìjdrotiaf upaf dxprdssiaf aj umiquityòtde gistafd G=O if M]HO? fu`` FRHs&

Uwa eoys ojtdr ifjdhtiaf '= epi), hd``s wdrd òmd`de witg MreT priar ta jixotiaf,

ikkufastoififc ofe JOHX ofo`ysis& ]dsu`t sgawf is rdprdsdftotivd aj 8 ifedpdfedft

dxpdrikdfts& d, FRHs sgawde rdeuhde opaptasis upaf dxprdssiaf aj umiquityòtde gistafdG=O ifM]HO? fu`` FRHs& FRHs wdrd hu`turde ofe ifjdhtde os if 'e)& Hd``s wdrd jixde,

ikkufastoifde witg ofti+ohtivotdehosposd 8 oftimaey ofe sumndhtde ta hafjaho` ikocifc&

Drrar mors ord sgawf os s&e& Xho`d mor> ?22 k

^gu dt o`& Rocd ?=


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript


13/14

Jicurd 5& Edrdprdssiaf aj sotd`ìtd EFO trofshriptiaf ahhurs if M]HO?+edjihidft mrdost hofhdrs

o, Godkotaxyìf!dasif stoififc ajM]HO?LA kausd mrdost hofhdr& MdhousdM]HO? LA

jdko`d kihd edvdàp kokkory tukars vdry rord`y, tgdsd kihd wdrd hrassde ifta o p48

gdtdrazycaus mohlcraufe jar ohhd`drotde tukaricdfdsis& KC, kokkory còfe jrak farko`

kausd ìttdrkotds& KCU, kokkory tukars jrak M]HO?LA kausd

'Mrho??,!+


14/14

Jicurd 4& Dhtapih dxprdssiaf aj sotd`ìtd EFO `does ta cdfakih ifstomiìty if gukof kokkorydpitgdìo` hd``s

o, O eiocrok aj tgd `dfti+viro` vdhtar dxprdssifc tgd gukof ar kausd sotd`ìtd EFO

sdqudfhd 'rde orraws) ufedr tgd G? prakatdr 'croy orraw)& m, h, e, Avdrdxprdssiaf aj

sotd`ìtd ]FO ifeuhde kitatih hotostrapgd 'm), hdftrasakd okpìjihotiaf 'h), gistafd G=Ox

pgaspgaryòtiaf 'e), if prikory GKDHs& d, Edjdhtivd kitatih hgdhlpaifts ifeuhde my

sotd`ìtd EFO avdrdxprdssiaf& 57g ojtdr trofseuhtiaf aj o dftivirus dxprdssifc gukof

sotd`ìtd EFO sdqudfhd witg jarwore eirdhtiaf 'gukof sotd`ìtd J), ar witg rdvdrsd eirdhtiaf

'gukof sotd`ìtd ]), ar kausd sotd`ìtd EFO sdqudfhd, ar of dkpty vdhtar, T+=AX hd``s wdrd

màhlde witg tgykieifd, ja`àwde my trdotkdft aj fahaeoza`d& Ugd hd``s wdrd stoifde witg

pgasga+gistafd G8 oftimaey ofe RI priar ta jàw hytakdtrih ofo`ysis& Ugd sgawf dxpdrikdft

is rdprdsdftotivd aj 8 ifedpdfedft rdpìhotds&

^gu dt o`& Rocd ?5


FIG+ROO

utgarKofushript


FIG+ROOutgar

Kofushript

BRCA1 tumor suppression occurs via heterochromatin mediatedsilencing

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