As soon as he p e-mRNA has been ansc ibed om
DNA in he nucleus, i is p ocessed in o a ma u e
ibonucleop o ein (mRNP) pa icle, which is compe en
o be expo ed om he nucleus. The THO complex, a
nuclea p o ein complex conse ed om yeas o
humans, is in ol ed in he biogenesis o mRNP pa icles
and unc ions a he in e ace be ween ansc ip ion and
RNA expo (Figu e 1).
Al hough i is now clea ha he THO complex has a
ole in RNA me abolism, he ini ial s udies ha ended in
he iden i ica ion o his key complex had no hing o do
wi h ansc ip ion, mRNP biogenesis o RNA expo . The
i s known componen o THO, Hp 1, was iden i ied
h ough a gene ic sc een o hype - ecom binan mu an s
in Saccha omyces ce e isiae. Subsequen gene ic and
molecula cha ac e iza ion o mu an s in which he hp 1
gene had been dele ed (hp 1∆ mu an s) linked he hp 1∆
hype - ecombina ion pheno ype o ansc ip ion and
showed ha Hp 1 was in ol ed in ansc ip ional
elonga ion. Tho2 was hen iden i ied as a high-copy-
numbe supp esso o hp 1∆. Yeas ho2∆ mu an s also
showed a s ong hype - ecombina ion pheno ype ha
was linked o a ansc ip ion elonga ion de ec ( e iewed
in [1]).
Hype - ecombina ion could ha e been seen as jus a
side e ec o he physiological consequences o THO
mu a ions, bu i u ned ou o e eal a ole o THO in
o ming an op imal mRNP pa icle, one ha p e en s he
nascen RNA om in e ac ing wi h he DNA empla e. In
hp 1∆ mu an s, he nascen RNA o ms an RNA-DNA
hyb id (R-loop) wi h he DNA empla e s and, while he
o he DNA s and emains single s anded; he o ma ion
o such ‘R-loops’ is linked o hype - ecombina ion
( e iewed in [1]). Resea ch om an inc easing numbe o
labo a o ies has e ealed THO o be a conse ed nuclea
ac o wi h a key unc ion in mRNP biogenesis and
expo as well as in de elopmen and cell di e en ia ion.
A ecen ly epo ed analysis [2] o a condi ional knockou
Abs ac
The THO complex is a key componen in he
co- ansc ip ional o ma ion o messenge
ibonucleopa icles ha a e compe en o be expo ed
om he nucleus, ye i s p ecise unc ion is unknown.
A ecen s udy in BMC Biology on he ole o he THOC5
subuni in cell physiology and mouse de elopmen
p o ides new clues o he ole o he THO complex in
cell di e en ia ion.
© 2010 BioMed Cen al L d
The THO complex as a key mRNP biogenesis ac o
in de elopmen and cell di e en ia ion
Sonia Jimeno and And és Aguile a*
See esea ch a icle h p://www.biomedcen al.com/1741-7007/8/1
MINIREVIEW
*Co espondence: [email p o ec ed]
Cen o Andaluz de Biología Molecula y Medicina Regene a i a, A . Amé ico
Vespucio s/n, 41092 Se illa, Spain
Figu e 1. The THO complex unc ions in mRNP biogenesis a
he in e ace be ween ansc ip ion and expo o mRNA om
he nucleus. P o eins a e shown wi h hei yeas name ollowed by
he name o he human homolog, whe e he wo di e , o Nab2,
M 2/p15, Sub2/UAP56, Mex67/TAP, Y a1/ALY, o wi h he yeas name
ollowed by he D osophila name o Sus1/ENY2. P o ein complexes
a e shown in capi al le e s: THO, THSC (also called TREX-2) and SAGA.
P o eins ha in e ac wi h each o he o be ween which a physical
connec ion has been epo ed a e in he same colo . Sus1 can ac
as a subuni o bo h THSC and SAGA complexes. Unlabeled p o eins
in g ay ep esen o he ac o s impo an o mRNP biogenesis and
expo . NPC, nuclea po e complex; RNAPII, RNA polyme ase II.
NPC
Mex67/
TAP
Cy oplasm
Nucleus
RNAPII
Nab2
mRNA
SAGA
Sus1/
ENY2
THSC/
TREX-2
M 2/
p15
Sus1/
ENY2
Sub2/
UAP56
Y a1/
ALY
THO
Jimeno and Aguile a Jou nal o Biology 2010, 9:6
h p://jbiol.com/con en /9/1/6
© 2010 BioMed Cen al L d
mouse o he THOC5 subuni o THO adds new pe -
spec i es o he ole o THO in di e en ia ion.
THO as a conse ed physical and unc ional uni
wi h a ole in mRNP biogenesis
The yeas THO complex was i s pu i ied om
Saccha omyces ce e isiae wi h a agged His(6)-Tho2
unde high-sal condi ions as a obus ou -subuni
complex o med by Tho2, Hp 1, M 1 and Thp2. Null
mu a ions in all THO componen s con e he same
pheno ypes - ansc ip ion impai men , hype -
ecombina ion and de ec i e RNA expo - indi ca ing
ha THO is a unc ional and physical uni . Fu he
pu i ica ion o he THO complex oge he wi h he
mRNA expo ac o s Y a1 and Sub2, he la e o which
is an RNA-dependen ATPase in ol ed in mRNA expo ,
in a la ge complex e med TREX ( ansc ip ion-expo
complex), and he iden i ica ion o Sub2 as a high-copy
supp esso o hp 1∆ led o he connec ion o THO wi h
RNA expo ( e iewed in [1]). This conclusion was
s eng h ened by he obse a ion ha sub2 mu an s led o
a simila ansc ip ion-dependen hype - ecombina ion
pheno ype o ha o THO-complex mu an s and ha
hese also show RNA-expo de ec s. Ne e heless, he
physical in e ac ions among he THO componen s a e
much s onge han hose wi h o he componen s o
TREX. THO is s able in high sal condi ions in he
absence o Y a1 and in which Sub2 is p esen in ace
amoun s ha can be de ec ed only by wes e n blo ing
( e iewed in [1]). Indeed, he in eg i y o he yeas THO
complex equi es Hp 1, Tho2, M 1 and Thp2 bu no
Sub2 [3]. The human o D osophila THO complexes also
con ain hTho2/THOC2, hHp 1/THOC1, Tex1/THOC3
and h ee addi ional subuni s called THOC5, THOC6
and THOC 7. The Sub2 o holog UAP56 can be de ec ed
in low amoun s in D osophila and is absen in human
cells immunodeple ed o hTho2, indica ing ha in hese
o ganisms he co e THO complex exis s as a sal - esis an
s able complex independen o UAP56 and Y a1 [4,5].
In yeas , THO binds o ac i e ch oma in in an RNA-
independen manne . A plausible scena io is as ollows
(Figu e 1): THO could be one o he i s playe s o ac
du ing ansc ip ion elonga ion o acili a e a co ec
mRNP o ma ion helping ec ui o he ac o s, such as
Sub2 o Mex67 [6]. O he RNA binding p o eins, such as
Y a1, which in e ac s wi h Sub2, and he Mex67-M 2
expo ac o , could ac a subsequen s eps in his
scena io o b ing he mRNP o he nuclea po e complex.
THO helps ec ui Mex67 o he mRNP h ough Hp 1,
an in e ac ion ha is egula ed by Rsp5, an ubiqui in
ligase ha polyubiqui ina es Hp 1 [7]. Close o he
nuclea po e complex, he THSC complex, also e med
TREX-2, could ha e an as-ye unknown unc ion in
mRNP biogenesis and expo . In e es ingly, mu a ions in
THSC con e he same pheno ypes o ansc ip ion
elonga ion impai men , de ec i e RNA expo and
ansc ip ion-dependen hype - ecombina ion as do
THO mu a ions ( e iewed in [1]).
Human THO associa es wi h p o eins o he spliceo-
some and wi h spliced RNAs, his la e in e ac ion being
independen o ansc ip ion [4,8]. Howe e , he e is also
e idence o ansc ip ion-dependen ec ui men o
THO o ch oma in in D osophila [9]. The ole o THO in
mRNP me abolism he e o e may be gene al among
euka yo es. The ecen obse a ion ha D osophila THO
complex in e ac s wi h ENY2, a p o ein p e iously
iden i ied as a ansc ip ional ac i a o ha in e ac s wi h
he SAGA ansc ip ion ac o , opens up he possibili y o
a co- ansc ip ional ac ion o THO in highe euka yo es
[9]. The impac o THO in RNA physiology, howe e ,
may go beyond ansc ip ion elonga ion and i s asso cia-
ed RNA me abolism s eps, as shown by he in ol emen
o THO in mRNA 3’ end p ocessing, whe he o no
di ec , and by he iden i ica ion in yeas THO mu an s o
a la ge nuclea mac omolecula s uc u e con aining
componen s o he nuclea po e complex and poly-
adenyla ion ac o s [10].
Func ion o THO in de elopmen and
di e en ia ion
The ele ance o THO in cell physiology has been clea ly
shown om yeas o humans. Yeas THO null mu an s
a e sick and slow g owe s and THO deple ion has a
nega i e e ec on g ow h a e o human and D osophila
cell lines. THO is equi ed o iabili y o he ea ly mouse
emb yo and o pos na al su i al, as de e mined by a
THOC1 knockou [2,11]. Whe he he ele ance o THO
unc ion is a consequence o a gene al, genome-wide ole
o whe he i s ole is limi ed o a subse o genes is s ill an
open ques ion. In humans and D osophila, a ious
s udies ha e shown ha THO is equi ed o he expo
o hea shock mRNAs, bu no hing is known abou o he
mRNAs. Simila ly, i is unknown whe he THO unc ion
is equi ed equally in di e en cell issues and h oughou
de elopmen and di e en ia ion. Impo an ly, howe e ,
THOC1 condi ional knockou mice e eal abno mal
es is de elopmen ha causes s e ili y [12]. Unde s and-
ing he ele ance o THO in de elopmen and issue
di e en ia ion as well as i s pu a i e impac in cance and
cell p oli e a ion should p o ide a be e unde s anding
o i s unc ional ole.
One s ep owa ds his unde s anding is he epo by
Mancini e al. [2], who ha e cons uc ed and cha ac e -
ized an in e e on-inducible c e- ecombinase based
condi ional THOC5 knockou mouse. THOC5 dele ion
causes dea h in he i s 2 weeks, simila o THOC1
dele ion. Mice wi h he condi ional knockou de elop
acu e leukocy openia (a educ ion in whi e blood cell
Jimeno and Aguile a Jou nal o Biology 2010, 9:6
h p://jbiol.com/con en /9/1/6
Page 2 o 3
numbe s) and anemia (a educ ion in ed blood cell
numbe s). The numbe o blood cells in pe iphe al blood
is educed d as ically; his is caused by apop osis o bone
ma ow cells and loss o commi ed myeloid p ogeni o
cells and o cells wi h long- e m econs i u ing po en ial.
The ans e o no mal bone ma ow cells escued 70% o
he mice om dea h. The da a [2] suppo he hypo hesis
ha THOC5 is c i ical in bone ma ow and in hema o-
poiesis, bu no o hepa ocy es and hea muscles. The
esul s a e consis en wi h p e ious wo k om his same
g oup ( e e enced in [2]) showing ha human THOC5
a ec s g anulocy e/mac ophage di e en ia ion and
adipo cy e di e en ia ion, and u he suppo he idea
ha he THO complex has a key ole no only in ea ly
emb yogenesis, bu also in di e en ia ion, as p e iously
epo ed wi h THOC1 knockou mice [11,12].
In he nea u u e i would be in e es ing o know
whe he he subuni s o he THO complex ha e di e en
oles in he di e en ia ion o dis inc cell ypes. And i
would ce ainly be impo an o unde s and how he ole
o he THO complex in de elopmen and di e en ia ion
is ela ed o i s molecula unc ion in mRNP biogenesis
and expo . Among he a ious possibili ies ha would
need o be in es iga ed o unde s and he ole o his
in iguing complex in di e en ia ion a e whe he o no
he THO complex has speci ic unc ions in di e en cell
ypes and how his migh be ela ed o pa icula unc-
ions ha THO could ha e o speci ic a ge mRNAs o
depending on he pu a i e THO p o ein modi ica ions
(phospho yla ion, ubiqui ina ion, and so on) ha migh
change i s pa e n o ac i i y.
Acknowledgemen s
We hank R Luna and AG Rondón o c i ical eading o he manusc ip . The
wo k o AA’s labo a o y is unded by he Spanish Minis y o Inno a ion and
Jun a de Andalucía.
Published: 28 Janua y 2010
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h p://jbiol.com/con en /9/1/6
doi:10.1186/jbiol217
Ci e his a icle as: Jimeno S, Aguile a A: The THO complex as a key mRNP
biogenesis ac o in de elopmen and cell di e en ia ion. Jou nal o Biology
2010, 9:6.
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