General transcription factors and subunits of RNA polymerase III

Article (PDF Available)inTranscription 1(3):130-135 · November 2010with25 Reads
DOI: 10.4161/trns.1.3.13192 · Source: PubMed
In the course of evolution of multi-cellular eukaryotes, paralogs of general transcription factors and RNA polymerase subunits emerged. Paralogs of transcription factors and of the RPC32 subunit of RNA polymerase III play important roles in cell type- and promoter-specific transcription. Here we discuss their respective functions.
Transcription 1:3, 130-135; November/December 2010; © 2010 Landes Bioscience
130 Transcription Volume 1 Issue 3
Key words: RNA polymerase III,
Submitted: 07/15/10
Revised: 07/29/10
Accepted: 07/30/10
Previously published online:
DOI: 10.4161/trns.1.3.13192
*Correspondence to: Martin Teichmann;
n the course of evolution of multi-
cellular eukaryotes, paralogs of gen-
eral transcription factors and RNA poly-
merase subunits emerged. Paralogs of
transcription factors and of the RPC32
subunit of RNA polymerase III play
important roles in cell type- and pro-
moter-specific transcription. Here we
discuss their respective functions.
Three distinct DNA-dependent RNA
polymerases (Pol I, Pol II and Pol III)
have been identified in eukaryotes more
than 40 years ago.
The presence of several
RNA polymerases in eukaryotes versus
one single RNA polymerase in prokary-
reflects increased complexity of the
transcription systems that may have been
necessary to accommodate the transcrip-
tion of an increased number of genes. Such
a gain in complexity may have allowed the
evolution of novel genes or groups of genes
that require the presence of more than one
polymerase for individual regulation.
A further level of complexity has been
added to transcription systems in arche-
bacteria and in eukaryotic cells by the
evolution of general transcription fac-
tors, replacing as an entity eubacterial
sigma factors. In addition, in multicellu-
lar eukaryotes, including insects and ver-
tebrates, paralogs of some of the general
transcription factors have evolved that
fulfill cell type or gene-specific functions.
Furthermore, paralogs of RNA poly-
merase subunits arose during evolution. As
a consequence, higher eukaryotes, includ-
ing plants and vertebrates, contain more
than three individual DNA-dependent
RNA polymerases.
Here, we review
General transcription factors and subunits of RNA polymerase III
Paralogs for promoter- and cell type-specific transcription in multicellular eukaryotes
Martin Teichmann,
* Giorgio Dieci,
Chiara Pascali
and Galina Boldina
Institut Européen de Chimie et Biologie (I.E.C.B.); Université de Bordeaux; Institut National de la Santé et de la Recherche Médicale (INSERM) U869;
Pessac, France;
Dipartimento di Biochimica e Biologia Molecolare; Università degli Studi di Parma; Viale G.P.; Usberti, Parma, Italy
our current knowledge of the existence
and function of paralogous components
of general transcription machineries and
particularly concentrate on components
that have been shown to function in Pol
III transcription or that may contribute
to Pol III transcription under certain cir-
cumstances (Table 1).
Pol III transcribes small untranslated
RNAs that are required for essential cel-
lular processes including the regulation
of transcription (7SK RNA, Alu RNAs),
RNA processing (U6 snRNA, RNase P
RNA, RNase MRP RNA) and translation
(5S rRNA, tRNAs). Distinct types of pro-
moters (Fig. 1A) are recognized by pro-
moter-specific sets of transcription factors
(Fig. 1B). In mammalian cells, the gene-
internal type 1 promoter is recognized
by the gene-specific transcription factor
TFIIIA, which in turn recruits TFIIIC,
TFIIIB-β and finally Pol III itself to the
5S gene. Gene-internal type 2 promot-
ers (e.g., tRNA-, Alu-, adenoviral VA1-
and VA2-genes) are directly recognized
by TFIIIC, allowing the recruitment of
TFIIIB-β and subsequently of Pol III.
Type 3 promoters (U6-, 7SK-, RNase P-,
RNase MRP-genes) are recognized by the
PSE-binding transcription factor (PTF;
also known as SNAPc and PBP), followed
by the recruitment of TFIIIB-α and of Pol
III (Fig. 1B).
Paralogs of TFIIIC Subunits
TFC7/t55/TFIIIC35-related factors. For
more than 10 years, Saccharomyces cere-
visiae (Sc) TFIIIC has been known to
be composed of six subunits (TFC4, Transcription 131
each of which consists of 5 alpha-helices
that together adopt a cyclin fold.
vertebrate cells, two distinct TFIIIB-
activities have been described that both
comprise TBP and BDP1, but that differ
by either containing TFIIB-related fac-
tor 1 (BRF1; component of TFIIIB-β;
transcription of type 1 and 2 promot-
ers; Fig. 1B) or TFIIB-related factor 2
(BRF2; component of TFIIIB-α).
TFIIIB-α is active in transcription of Pol
III genes with gene regulatory elements
that are entirely located upstream of the
transcription initiation site (type 3 pro-
moter; Fig. 1B) and the BRF2 component
of TFIIIB-α has also been cross-linked
to genes that contain a combination of
gene-internal and gene-external promoter
The evolution of a second
TFIIB-related factor at the emergence of
vertebrates may have permitted or may
have been tolerated by the co-evolution
of a novel Pol III promoter type. With
respect to the question of whether the
evolution of BRF2 led to the co-evolution
of a novel promoter type it is notewor-
thy to mention that promoter elements
upstream of the transcription initiation
site have also been identified for the U6
and 7SK genes in Drosophila melanogaster
(Dm; Fig. 1A).
Despite the gene regula-
tory elements being located upstream of
the transcription initiation site, only one
isoform of a DmTFIIB-related factor has
been described. These results indicate that
the evolution of upstream promoters in
the Pol III transcription system, at least in
insects, may not have been driven by the
evolution of a second isoform of a TFIIB-
related factor, although we cannot exclude
that BRF2 sequences may have been lost
in the course of evolution in these species.
If ever the appearance of type 3 promot-
ers may not be attributable to the evolu-
tion of BRF2 it may be asked whether
BRF1 or BRF2 possess other gene- or cell
type-specific functions. Today, we only
know a single gene in vertebrates (coding
for BC200 RNA in humans or the func-
tionally analogous BC1 RNA in rodents)
that is transcribed by Pol III and that
shows neuronal-specific expression.
sequencing and ChIP-on-CHIP experi-
ments demonstrated that the BC200 gene
is in physical contact with Pol III.
ChIP sequencing further showed the
regions of homology to both a subunit of
TFIIIC and a subunit of PTF raises the
possibility that at least one subunit of
TFIIIC and of PTF may have evolved from
a common ancestor protein. Interestingly,
genomes of Dpp and Dp encode in addi-
tion a smaller protein of 150 amino acids
(XP_002134843 [Dpp]; XP_002021117
[Dp]) that is highly related (82% identical
and 92% homologous) to the N-terminal
144 amino acids of the two larger pro-
teins (537 amino acids [Dp] or 538 amino
acids [Dpp]) and that may represent the
TFC7 subunit of TFIIIC in the respec-
tive Drosophila (Fig. 2). Importantly, the
proteins of Dpp and Dp, containing the
TFIIIC- and the zf-SNAP_C-signature,
were the only proteins related to Drosophila
melanogaster (Dm)PSEA-binding protein
49 kD, suggesting that these proteins par-
ticipate in UsnRNA transcription in these
species. Thus, these proteins may be both
considered as orthologs of the Dm PSEA-
binding protein 49 kD and as paralogs of
Paralogs of TFIIIB Subunits
ScTFIIIB is composed of three subunits,
the TATA-binding protein (TBP), TFIIB-
related factor 1 (BRF1) and B double prime
1 (BDP1). Together with TFIIIA, TFIIIC
and Pol III, these three components are
required and sufficient for reconstituting
transcription from all Pol III promoters in
ScBRF1 is a paralog of TFIIB and it
possesses a structure that is similar to that
of TFIIB. It contains an N-terminal zinc
ribbon and two direct imperfect repeats,
TFC1, TFC7, TFC8, TFC3 and TFC6),
whereas only five subunits had been
described in humans (TFIIIC102, 63,
90, 220 and 110; Fig. 1B). Recently, we
identified and characterized the sixth sub-
unit of human (Hs) TFIIIC (TFIIIC35;
Fig. 1B), which is orthologous to
Saccharomyces cerevisiae (Sc) TFC7 (τ55).
We identified TFIIIC35 through a Psi-
Blast search by using a 34 amino acid
sequence of a yeast Schizosaccharomyces
pombe (Sp) protein as a seed, which showed
modest sequence conservation with amino
acids 317–350 of ScTFC7.
This 34 amino
acid sequence also overlaps with the Pfam
10419:TFIIIC_subunit signature.
order to identify novel proteins that may
represent paralogs of TFIIIC subunits,
we now performed a Psi-Blast search
(BLOSUM 62; exclude Saccharomyceta
from search) with amino acids 321–364
of ScTFC7. Upon the second iteration,
we identified two proteins in two dis-
tinct drosophilidae (XP_001360915.2
in Drosophila pseudoobscura pseudoob-
scura [Dpp] and XP_002017815.1 in
Drosophila persimilis [Dp]) that exhibited
34% sequence identity and 62% sequence
homology of amino acids 39 to 72 with
the amino acids 321–354 of Sc TFC7
(Fig. 2). Surprisingly, amino acids 259 to
510 of the two Drosophila proteins con-
tained a second signature that has been
found to be conserved in PTFβ/SNAP50
subunits of PTF/SNAPc/PBP (29% iden-
tity and 46% homology to amino acids
155 to 402 of human PTFβ); pfam12251:
zf-SNAP50_C; Fig. 2). The presence of a
protein in Dp and in Dpp that contains
Table 1. Components of the general Saccharomyces cerevisiae Pol III transcription machinery and
their paralogs in Drosophila
Transcription factor/
polymerase subunit
Orthologous and/or paralogous transcription factors
Saccharomyces cerevisiae Drosophila Vertebrates
XP_002134843 and XP_001360915 in Dpp.
XP_002021117 and XP_002017815 in Dp.
(NP_788522.1 in Dm)
The Dpp and Dp proteins XP_001360915 and XP_002017815 are 98% identical and 99%
homologous. The proteins XP_002134843 and XP_002021117 are identical. Dp, Drosophila
persimilis; Dpp, Drosophila pseudoobscura pseudoobscura; Dm, Drosophila melanogaster and
132 Transcription Volume 1 Issue 3
Figure 1. For gure legend, see page 133. Transcription 133
TRF3/TBP2. A gene encoding TRF3 was
found in a variety of metazoans, includ-
ing humans, mice, frogs and fish. Specific
functions for TRF3 in differentiation of
mouse myoblasts, in zebrafish hemato-
poiesis and in Xenopus or mouse oocytes
have been suggested.
knockout studies showed that mice had no
apparent phenotype except females being
sterile due to defective folliculogenesis.
A possible involvement of TRF3/TBP2
in Pol III transcription has not yet been
reported. However, the high degree of
conservation between the C-terminal part
of human TBP (residues 141–337) and
TRF3 (residues 184–374; 92% identity
and 95% homology) makes it likely that
TRF3 may be functional in Pol III tran-
scription. Moreover, residues in ScTBP
that have been reported to be critical
for the interaction with ScBRF1 (S261;
D263; S282; E284; E286; L287; R299;
V306) or with ScBdp1 (H277) have been
conserved in both, HsTBP and HsTRF3/
In line with the possibility that
TRF3/TBP2 may be able to replace TBP
transcription of certain genes may not
depend on TBP.
Although first described as a cell type-
specific factor, TRF1 turned later out to
be widely expressed in Dm and to replace
TBP for transcription by Pol III,
was confirmed by ChIP-on-CHIP analy-
ses using afnity-purified anti-TRF1
antibodies and Drosophila genome tiling
In addition to its essential func-
tions in Dm Pol III transcription, TRF1
has also been implicated in the transcrip-
tion of a small subset of Pol II genes.
ortholog of TRF1 could hitherto be iden-
tified in species other than insects.
Several years later, a second para-
log of TBP was identified in mammals,
Drosophila melanogaster, Caenorhabditis
elegans and other metazoans.
was shown to be involved in tran-
scription by Pol II,
but it was dem-
onstrated that recombinant HsTRF2
was inactive in Pol III transcription in
The third and latest member of the
TBP-family that has been identified is
presence of BDP1 at the BC200 genomic
locus. Interestingly, however, neither
BRF1, nor BRF2 could be detected at the
BC200 gene locus.
This could merely
be a technical problem, but it could also
indicate that transcription initiation of the
BC200 gene may be independent of BRF1
and BRF2. In this case, another, hitherto
unidentified protein may replace BRF1/
BRF2 for transcription of the BC200 gene
in neurons. Taken together, the emergence
of BRF1 and BRF2 during evolution led to
the appearance of two isoforms of TFIIIB
with promoter-specific functions.
TBP-related factors. TBP was once
assumed to be a universal transcrip-
tion factor.
This point of view was well
understandable at that time, because the
discovery that TBP participates in tran-
scription of all three RNA polymerases
would not have been anticipated some
years earlier and TBP was thought to be
generally indispensable for transcription.
However since then, several paralogs of
TBP have been identified (TRF1; TRF2;
TRF3) and their discovery indicated that
Figure 1 (See opposite page). (A) RNA polymerase III promoter types in humans (Hs), Drosophila melanogaster (Dm) and Saccharomyces cerevisiae (Sc).
Type 1 and 2 promoters are similar, but U6 promoters are dierent in the three species. The complete set of genes that utilize the distinct promoter
types have been determined.
(B) Promoters and transcription factors of the human (vertebrate) Pol III transcription machinery. Subunits of the PSE-
binding transcription factor (PTF) are indicated by their PTF nomenclature and the molecular masses of the corresponding SNAPc subunits. SNAPc19
has not been reported in PTF.
Figure 2. Schematic representation of the amino acid homology of a Drosophila pseudoobscura pseudoobscura protein (Genbank accession #
XP_001360915) with ScTFC7, with HsPTFβ and with a Drosophila pseudoobscura pseudoobscura protein (Genbank accession # XP_002134843). The
percentage of identical amino acids is indicated by “id” and of homologous amino acids by “ho.” The numbers of amino acids of the individual
proteins, as well as the regions showing homology in between individual proteins are appropriately indicated. The Pfam signature 12251:zf-SNAP50_C
is found in HsPTFβ (amino acids 201–407) and in Dpp XP_001360915 (amino acids 309–515). The Pfam signature 10419:TFIIIC_subunit is contained in
ScTFC7 (amino acids 317–351) and the Dpp proteins XP_001360915 and XP_002134843 (amino acids 35–69 in both proteins).
134 Transcription Volume 1 Issue 3
to determine how RPC32α/Pol IIIα is
involved in cellular differentiation and
de-differentiation processes and whether
the existence of two Pol III isoforms is
somehow related to cell type- or stage-
specific expression of both classical house-
and non-canonical regulatory
Pol III genes.
This work has been supported by grants
from the Conseil Régional dAquitaine
and the European Regional Development
Fund (to M.T.); by grants from the
Agence Nationale de la Recherche (ANR)
“REGPOLSTRESS” (to M.T.), the
Ligue Contre le Cancer-Comités Gironde
and Dordogne (to M.T.), the Italian
Ministry of Education, University and
Research (PRIN 2007 grant to G.D.), the
AICCRE-Regione Emilia Romagna (to
G.D.). C.P. was supported by a doctoral
fellowship from the “Università Italo-
Francese/Universi Franco-Italienne.
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product enhances its probability of being
If ever such genes exist, does
their transcription depend on known or
novel promoter structures (types 1–3) and
transcription factors (TFIIIA, TFIIIC,
TFIIIB, PTF)? Today, these questions
cannot be answered but will be of interest
for future research.
Furthermore, from the expression
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it may be inferred
that Pol IIIα has a role in maintaining
embryonic stem cells in an undifferenti-
ated state. Therefore, it will be of interest
in Pol III transcription, it has been sug-
gested that TRF3/TBP2 may be a TBP
replacement factor in cells that contain
low levels of TBP.
Paralogs of RNA
Polymerase III Subunits
Pol III is composed of 17 subunits. Five
of these subunits are shared with Pol I
and II, two with Pol I only (with paralo-
gous subunits in Pol II) and another five
subunits are paralogous to subunits of
Pol I and Pol II. However, five subunits
are Pol III-specific and no paralogous
subunits have been identified in Pols I
and II. Recently, it has been proposed
that four of the five Pol III-specific sub-
units (POLR3E/HsRPC80, POLR3D/
POLR3F/HsRPC39) exhibit sequence/
structure homology to the heterodimeric
general Pol II transcription factors TFIIE
and TFIIF and that they may be consid-
ered as permanently recruited forms of
these transcription factors.
HsRPC32 is the only Pol III subunit for
which no homologous polypeptide has
been identified within the Pol I and Pol II
transcription machineries.
RPC32-related factors. As pointed
out above, the emergence of three
DNA-dependent RNA polymerases in
eukaryotes may have allowed a more
sophisticated regulation of individual sets
of genes. Recently, two distinct isoforms
of human Pol III have been reported,
which may allow even further specializa-
tion for transcription of individual genes.
The two isoforms of human Pol III differ
at least in containing either the RPC32α
(Pol IIIα) or the RPC32β (Pol IIIβ) sub-
unit, and they exhibit isoform-specific
expression patterns in distinct cell types.
Northern blot analyses of multiple human
tissues and cell lines demonstrated that
Pol IIIβ is widely expressed, whereas Pol
IIIα expression is only detectable in sev-
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    • "Yeast Pol III consists of 17 subunits which have structural and functional homologs in human cells. Transcription of tRNA genes requires the multisubunit initiation factors TFIIIB and TFIIIC which specifically bind to internal control regions [1] [2]. "
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    • "TBP and two RNAP-III-specific TAFs (BrfI and BdpI) assemble into the TFIIIB complex, which is involved in RNAP-III transcription. In vertebrates, there are two versions of TFIIIB complex containing either BrfI or its homolog BrfII (reviewed in [16]). Besides TFIIIB, TBP also interacts with the snRNA activating protein complex (SNAPc) at the human U6 promoter [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: ABSTRACT: TATA binding protein (TBP) is a key component of the eukaryotic transcription initiation machinery. It functions in several complexes involved in core promoter recognition and assembly of the pre-initiation complex. Through gene duplication eukaryotes have expanded their repertoire of TATA binding proteins, leading to a variable composition of the transcription machinery. In vertebrates this repertoire consists of TBP, TBP-like factor (TLF, also known as TBPL1, TRF2) and TBP2 (also known as TBPL2, TRF3). All three factors are essential, with TLF and TBP2 playing important roles in development and differentiation, in particular gametogenesis and early embryonic development, whereas TBP dominates somatic cell transcription. TBP-related factors may compete for promoters when co-expressed, but also show preferential interactions with subsets of promoters. Initiation factor switching occurs on account of differential expression of these proteins in gametes, embryos and somatic cells. Paralogs of TFIIA and TAF subunits account for additional variation in the transcription initiation complex. This variation in core promoter recognition accommodates the expanded regulatory capacity and specificity required for germ cells and embryonic development in higher eukaryotes.
    Full-text · Article · Jun 2011
    • "These findings anticipated the crucial discovery of TBP as a universal core TF, participating in the inner workings of all the three eukaryotic transcription machineries (Hernandez, 1993; Rigby, 1993; White et al., 1992), a property that was also already known for five subunits shared by the three nuclear RNA polymerases (Carles et al., 1991). Since then, the sharing of components by the three transcription systems, or the presence of paralogous polypeptides playing similar functions in different systems, has perhaps become less surprising, but not less challenging in terms of mechanistic interpretation (Carter and Drouin, 2010; Geiger et al., 2010; Kassavetis et al., 2010; Lefevre et al., 2011; Teichmann et al., 2010). As significant examples, we mention in particular the Pol II elongation factor TFIIS and the Pol II coactivator protein Sub1, that have recently been located at Pol IIItranscribed genes in S. cerevisiae by genome-wide studies, but whose function in transcription of these genes is only partially understood (Ghavi-Helm et al., 2008; Rosonina et al., 2009; Tavenet et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Eukaryotic genomes are punctuated by a multitude of tiny genetic elements, that share the property of being recognized and transcribed by the RNA polymerase (Pol) III machinery to produce a variety of small, abundant non-protein-coding (nc) RNAs (tRNAs, 5S rRNA, U6 snRNA and many others). The highly selective, efficient and localized action of Pol III at its minute genomic targets is made possible by a handful of cis-acting regulatory elements, located within the transcribed region (where they are bound by the multisubunit assembly factor TFIIIC) and/or upstream of the transcription start site. Most of them participate directly or indirectly in the ultimate recruitment of TFIIIB, a key multiprotein initiation factor able to direct, once assembled, multiple transcription cycles by Pol III. But the peculiar efficiency and selectivity of Pol III transcription also depends on its ability to recognize very simple and precisely positioned termination signals. Studies in the last few years have significantly expanded the set of known Pol III-associated loci in genomes and, concomitantly, have revealed unexpected features of Pol III cis-regulatory elements in terms of variety, function, genomic location and potential contribution to transcriptome complexity. Here we review, in a historical perspective, well established and newly acquired knowledge about Pol III transcription control elements, with the aim of providing a useful reference for future studies of the Pol III system, which we anticipate will be numerous and intriguing for years to come.
    Full-text · Article · Jun 2011
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