ATAC-king the complexity of SAGA
Gianpiero Spedale, H.Th. Marc Timmers,1,4and W.W.M. Pim Pijnappel1,2,3
Molecular Cancer Research, Netherlands Proteomics Center, University Medical Center Utrecht, 3584 CG Utrecht,
The yeast SAGA (Spt–Ada–Gcn5–acetyltransferase) coac-
tivator complex exerts functions in gene expression,
including activator interaction, histone acetylation, his-
tone deubiquitination, mRNA export, chromatin recogni-
tion, and regulation of the basal transcription machinery.
These diverse functions involve distinct modules within
this multiprotein complex. It has now become clear that
yeast SAGA has diverged during metazoan evolution
into two related complexes, SAGA and ATAC, which
exist in two flavors in vertebrates. The compositions of
metazoan ATAC and SAGA complexes have been char-
acterized, and functional analyses indicate that these
complexes have important but distinct roles in transcrip-
tion, histone modification, signaling pathways, and cell
Supplemental material is available for this article.
Almost two decades ago, Allis and coworkers (Brownell
and Allis 1995; Brownell et al. 1996) discovered that an
;55-kDa protein purified from the macronuclei of the
ciliated protozoan Tetrahymena thermophila exhibited
acetyltransferase activity toward histones. This protein
was orthologous to the yeast transcriptional coactivator
Gcn5 that was found to be present in a protein complex
with Ada2. The Ada2 protein was identified in genetic
screens for transcriptional coactivators (Berger et al. 1992;
Marcus et al. 1994). These two key discoveries provided
the basis for the concept that histone acetylation and
transcription are intimately connected. Within chroma-
tin, DNA is wrapped around histone octamers consisting
of the histone H3–H4 tetramer associated with two H2A–
H2B dimers to form discrete nucleosome units. These
nucleosomes are the basic repeating unit of chromatin
and restrict access by protein complexes involved in
DNA-mediated cellular transactions. The N termini of
these core histones protrude from the nucleosome particle
and are subjected to a variety of post-translational modifi-
cations, including acetylation (Berger 2007). Histone acety-
lation has been one of the most studied histone modifica-
tions, and the histone acetyltransferase (HAT) complexes
involved have become major research topics. Acetylation
modifies the physical–chemical properties of the chromatin
fiber, but it also provides interaction sites for a myriad of
binding proteins. These ‘‘readers’’ typically use a bromodo-
main for acetyl-lysine interactions (Mujtaba et al. 2007). In
cellular systems, histone acetylation is a dynamic process,
which has attracted particular interest from a clinical per-
spective (Rodriguez-Paredes and Esteller 2011). Drugs inhib-
iting the enzymes known as the ‘‘erasers’’ of acetylation, the
histone deacetylases (HDACs), are effective in particular
types of lymphomas. Very recently, molecules inhibiting
acetyl-lysine binding of the bromodomain-containing Brd2
and Brd4 proteins have been shown to be effective suppres-
interface between gene regulation and chromatin mod-
ification has expanded enormously and has revolutionized
molecular models of gene expression, genome structure,
(epi)genetic inheritance, and human disease.
A few years after their characterization, the highly con-
served Gcn5 HAT and Ada2 proteins were found to be
part of a multiprotein complex named SAGA (Spt–Ada–
Gcn5–acetyltransferase) (Grant et al. 1997). The unveiling
of the modular architecture of the SAGA complex has
permitted deciphering of its multifunctional role (Sterner
et al. 1999). Characterization of the yeast SAGA complex
revealed several layers of transcription-related functions,
including transcription initiation and elongation, histone
ubiquitination, and TATA-binding protein (TBP) interac-
tions. In addition, SAGA has nontranscriptional roles, in-
cludingmRNAexport(Rodriguez-Navarro et al. 2004) and
maintenance of DNA integrity (Atanassov et al. 2009;
Guo et al. 2011). Recent evidence indicates that the yeast
SAGA complex has diverged during evolution in several
served SAGA variants and more distantly related ATAC
variants (Guelman et al. 2006a). We refer to these com-
plexes collectively as SAGA-like complexes because they
share a common catalytic core. Many aspects of their
[Keywords: chromatin; histone acetylation; SAGA; TFIID; transcription
1These authors contributed equally to this work.
Present addresses:2Department of Pediatrics, Center for Lysosomal and
Metabolic Diseases, Erasmus Medical Center, Dr. Molewaterplein 50,
3015 GE Rotterdam, The Netherlands;3Department of Clinical Genetics,
Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center,
Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.184705.111.
GENES & DEVELOPMENT 26:527–541 ? 2012 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/12; www.genesdev.org527
transcriptional and nontranscriptional functions have
been covered in excellent reviews (Nagy and Tora 2007;
Rodriguez-Navarro 2009; Koutelou et al. 2010; Rodriguez-
Navarro and Hurt 2011; Weake and Workman 2011).
Here, we focus on the evolutionary divergence of
SAGA-like complexes in the context of transcriptional
Compositions and post-translational modifications
of SAGA-like complexes
We first describe how the yeast SAGA complex has
diverged with respect to composition and conservation
of protein domains. The subunit comparison indicates
two main points. First, SAGA architecture is strongly
conserved between yeast, flies, and mammals (Fig. 1).
Second, the number of SAGA-like complexes increased
during evolution (Fig. 2). Yeast contains one SAGA
complex (and its subcomplexes/proteolytic derivatives)
(see below), insects contain two SAGA-like complexes
(SAGA itself and ATAC), and mammals contain four
main SAGA-like complexes (SAGA itself with Gcn5 or
the highly related HAT Pcaf, and ATAC with Gcn5 or
It is well known that diversification of protein function
can be accomplished by the duplication and mutation of
ancestor genes (Soskine and Tawfik 2010). Diversification
of protein complexes seems to be a common theme for
and using SMART (http://smart.embl-heidelberg.de). Homologous domains of published domains were in some cases refined by alignments
using ClustalW (http://www.ebi.ac.uk/Tools/msa/clustalw2) or BLAST. The prefix ‘‘y’’ indicates Saccharomyces cerevisiae, ‘‘d’’
indicates Drosophila melanogaster, and ‘‘h’’ indicates Homo sapiens.
Composition and domain organization of SAGA and ATAC. Protein domains have been assigned based on published data
Spedale et al.
528GENES & DEVELOPMENT
increasing functional complexity during evolution. For
example, the six Set1/MLL complexes in mammals have
one ancestor complex, termed Set1C/COMPASS, in yeast
(Miller et al. 2001; Roguev et al. 2001; Smith et al. 2011).
Also, the Sin3 complex involved in transcriptional re-
pression and histone deacetylation exists in one complex
in yeast, while mammals contain two related but distinct
complexes (Sin3A and Sin3B) (Hayakawa and Nakayama
2011). In many cases, overall architecture has been
conserved for related protein complexes, and the compo-
sition of modules and domains has diversified. This
seems particularly relevant for SAGA-like complexes,
which underwent important changes during evolution,
and we hypothesize that these changes and expansions
are used for functional cellular specialization involved in
development and homeostasis of metazoan organisms. In
addition, most SAGA and ATAC subunits are subjected
to extensive post-translational modification, including
phosphorylation and acetylation, which are listed in
Supplemental Table S1. In most cases, the functions of
these modifications have not been determined, but we
provide them as resources for future investigations, as
these modifications could be end points of signal trans-
assembly of ATAC or SAGA, respectively. Some of the chromatin interaction modules are indicated: The Tudor domain in Sgf29 binds
H3K4me3, and the bromodomain in Gcn5 and in Pcaf binds acetylated histones. HATactivity is provided by Gcn5 or Pcaf. The second
HAT in ATAC, Atac2, is also indicated.
Divergence and multiplication of SAGA-like complexes during evolution. Incorporation of Ada2a or Ada2b determines
GENES & DEVELOPMENT529
Structure and function of SAGA and ATAC
Diversification of SAGA and links to other
The yeast SAGA complex is composed of 19 subunits
(Mischerikow et al. 2009; Lee et al. 2011) with a total
mass of ;2 MDa, which are organized into a five-domain
structure as indicated by a three-dimensional (3D) model
reconstructed from (immuno-)EM images (Wu et al.
2004). Each domain harbors specific SAGA functions
(Timmers and Tora 2005; Lee et al. 2011). The transcrip-
tion factor interaction domain localizes to the foot of the
structure containing the Tra1 subunit. Together with
Spt20 and Spt7, the subunits Ada1, Taf5, Taf6, Taf9,
Taf10, and Taf12 are believed to form the structural core
of SAGA. The Taf subunits received particular interest, as
they are also integral subunits of the basal transcription
factor TFIID. Interaction with the TBP resides with Spt3
and Spt8 (Eisenmann et al. 1992). The HAT function
resides in a domain containing Gcn5, Ada2, Ada3, and
Sgf29, whereas the histone H2B deubiquitination (DUB)
module harbors Usp8, Sgf11, Sgf73, and Sus1. Interest-
ingly, Sus1 is also part of the mRNA export complex
TREX-2 (in yeast)/AMEX (in metazoans). This property
connects SAGA to a process called gene gating, in which
certain transcribed genes are located near nuclear pore
complexes to increase nuclear mRNA export. While
first identified in yeast (Rodriguez-Navarro et al. 2004)
and confirmed in Drosophila (Kurshakova et al. 2007),
the relevance of this process for mammalian gene ex-
pression remains to be established (Garcia-Oliver et al.
An important change in SAGA function stems from the
fact that no ortholog of the SPT8 gene is present in the
genomes of metazoans. In addition, higher eukaryotes
contain a truncated homolog of yeast Spt7 lacking the
C terminus. In yeast, a variant of SAGA exists, termed
SLIK/SALSA (Belotserkovskaya et al. 2000; Pray-Grant
et al. 2002; Sterner et al. 2002; Wu and Winston 2002), in
which the C terminus of Spt7 is proteolytically cleaved
by Pep4 (Spedale et al. 2010), resulting in the removal of
the Spt8-binding domain. SLIK/SALSA has altered prop-
erties compared with SAGA, in particular with regard to
the TBP interaction module. This consists of Spt3 and
Spt8 in SAGA (Eisenmann et al. 1992) and has now been
weakened in SLIK/SALSA due to the absence of Spt8
(Sermwittayawong and Tan 2006; Laprade et al. 2007;
Mischerikow et al. 2009). As noted previously (Nagy et al.
2009), metazoan SAGA more closely resembles the yeast
SLIK/SALSA complex because it contains a C-terminally
truncated version of Spt7 and lacks Spt8. This may have
consequences for the TBP-interacting properties of meta-
zoan SAGA, which may be weaker compared with yeast
SAGA. Indeed, while TBP can be easily detected in
preparations of yeast SAGA, it is absent from human
SAGA (Wieczorek et al. 1998).
Most domains in SAGA subunits are remarkably
conserved (Fig. 1). Exceptions are listed hereafter. First
and as stated above, metazoan homologs of Spt7 are
C-terminally truncated. This has led to loss of the
histone fold (HF) and bromodomain in the fly ortholog.
The HF is a conserved motif that is present in the core
nucleosomal histones and selected transcription factors.
The HF can mediate protein dimerization (Luger et al.
1997; Gangloff et al. 2001). Since the HF of yeast Spt7
forms a heterodimer with Taf10 in SAGA (see below), this
loss is expected to have structural consequences. Loss of
the bromodomain may affect the interaction of fly SAGA
with acetylated proteins, including histones (Hassan et al.
2002). Human Spt7 does not contain a classical bromo-
domain or HF, but rather a bromo-associated domain that
resembles a histone-like fold. Second, Taf5 from yeast
contains a LisH domain, which has been implicated in
dimerization. This domain is absent from its counter-
parts in flies and humans, WDA and Taf5L, respectively
(Ogryzko et al. 1998; Guelman et al. 2006b). In contrast,
human Taf5, which exclusively assembles into the TFIID
complex, contains a LisH domain. Third, and similar to
this, yeast Taf6 and human Taf6L (Ogryzko et al. 1998)
contain the DUF1546 domain of unknown function,
which is absent from its fly counterpart, SAF6 (Weake
et al. 2009). Fourth, the human ortholog of yeast Sgf11,
ATXN7L3, contains an atypical zinc finger, termed a spi-
nocerebellar ataxia type 7 (SCA7) domain, at its C ter-
minus. This is lacking in flies and yeast (Kohler et al.
2008; Weake et al. 2008, 2009; Bonnet et al. 2010). Fifth,
yeast Sgf73 and its human ortholog, ATXN7, also contain
a SCA7 domain, but again, this is missing in its fly
counterpart (Kohler et al. 2008; Weake et al. 2009; Bonnet
et al. 2010). Interestingly, the SCA7 domain of ATXN7/
hSgf73 but not of ATXN7L3/hSgf11 can interact with
nucleosomes (Bonnet et al. 2010). Finally, the SWIRM
domain functioning in protein–protein and protein–DNA
interactions (see below) is missing in Ada2b from flies
(Muratoglu et al. 2003). Taken together, these structural
comparisons suggest that the interaction properties of
SAGA complexes may differ between species.
During evolution, gene duplications have occurred for
TAF5, TAF6, TAF9, TAF10, GCN5, and ADA2. In yeast,
the Taf5 and Taf6 proteins are part of SAGA but also of
the related TFIID complex (Grant et al. 1998). In mam-
mals, the genes for TAF5 and TAF6 have been duplicated
and have diverged into TAF5L and TAF6L. The Taf5 and
Taf6 proteins remain specific for TFIID, while Taf5L and
Taf6L are specific for SAGA (Ogryzko et al. 1998). In-
terestingly, flies have diverged in another direction.
While the TAF5L and TAF6L genes exist, their products
are not part of SAGA in this species (Guelman et al.
2006b; Weake et al. 2009). Instead, SAGA in flies contains
Wda rather than Taf5 or Taf5L, and Saf6 rather than Taf6
or Taf6L. It is not known whether fly Taf5L and Taf6L
assemble into alternative transcription complexes. Since
both proteins are highly expressed in fly testis, it may be
that they are involved in the formation of testis-specific
TFIID or SAGA-like complexes (Guelman et al. 2006b;
Weake et al. 2009). TAF9 has been duplicated in humans
into the TAF9 and TAF9B genes. Taf9 and Taf9b have
partially overlapping functions (Frontini et al. 2005). Both
proteins can incorporate into SAGA and TFIID com-
plexes, further increasing the number of complexes in
humans. Duplication of TAF10 in flies but not in humans
Spedale et al.
530GENES & DEVELOPMENT
led to two genes: TAF10, which encodes a TFIID subunit,
and TAF10B, which encodes a SAGA subunit.
Only one GCN5 gene is present in yeast, while flies
and humans contain a larger homolog that encodes an
N-terminal extension harboring a PCAF homology do-
main (Koutelou et al. 2010; Nagy et al. 2010). In humans,
GCN5 has been duplicated and diverged to generate the
PCAF gene. The Gcn5 and Pcaf proteins are very similar,
and both harbor the PCAF homology domain. Both Gcn5
and Pcaf can assemble into human SAGA complexes in
a mutually exclusive manner (Krebs et al. 2010). Pcaf was
named according to its original identification as a p300/
CBP-associated factor (Yang et al. 1996). In retrospect,
this name is confusing, as SAGA-like complexes lack
p300 or CBP. ADA2 represents another gene that has been
duplicated in evolution. One ADA2 gene exists in the
yeast genome encoding a subunit that is part of both the
SAGA and the smaller ADA complex (Lee et al. 2011). In
many but not all metazoans, this gene has been duplicated
into ADA2A and ADA2B. At this point, the separation
between SAGA and ATAC begins. The fly and human
Ada2b proteins are exclusively present in SAGA, while
Ada2a is specific for ATAC. The entire ATAC complex is
specific for higher eukaryotes and is absent from yeast
(Barlev et al. 2003; Muratoglu et al. 2003; Suganuma et al.
2008; Wang et al. 2008; Orpinell et al. 2010).
Diversification of SAGA into ATAC and links to other
ATAC has emerged later during evolution from SAGA
and is exclusive to multicellular eukaryotes. This may be
related to the increased complexity of metazoans. SAGA
and ATAC diversified from a single variant in flies into
two human variants through duplication of its HAT
subunit. Interesting physical links exist with related
chromatin and transcription complexes. Important dif-
ferences have been noted between the fly and human
ATAC complexes with regard to conserved domains and
subunit composition (Suganuma et al. 2008; Wang et al.
2008; Guelman et al. 2009; Nagy et al. 2009).
ATAC shares a core with SAGA that consists of Ada3,
Sgf29, and Gcn5 in flies, or Gcn5/Pcaf in human. This
results in the occurrence of one ATAC variant in flies,
whereas two variants, with Gcn5 or with Pcaf, exist in
humans (Fig. 2). In addition to a shared catalytic core,
nine to 10 ATAC-specific subunits exist. A few differ-
ences with regard to subunit composition exist between
the fly and human complexes. Atac3 has been identified
as a bona fide component of fly ATAC by reciprocal
immunoprecipitation and mass spectrometry analysis
(Suganuma et al. 2008). However, this protein seems to
be a fly-specific subunit, since no orthologs have been
detected in ATAC purifications from human cells (Wang
et al. 2008; Nagy et al. 2009). Hcf1, which is also present
in other chromatin-modifying complexes (Wysocka et al.
2003), was found as a specific subunit of ATAC in flies
(Suganuma et al. 2008). Human Hcf1 has been detected in
both ATAC and SAGA purifications (Wang et al. 2008),
but other purifications from human cells failed to detect
Hcf1 in either SAGA or ATAC (Guelman et al. 2009;
Nagy et al. 2010). This suggests that Hcf1 may not be
a stable ATAC or SAGA subunit in human cells, but
rather interacts in adynamic manner.Additional proteins
have been identified in ATAC purifications from human
but not insect cells. These include Pole4, which is also
a subunit of the DNA polymerase e complex; hMap3k7,
which links ATAC to mitogen-activated protein kinase
(MAPK) signaling; and Ubap2l, a protein with unknown
function (Wang et al. 2008).
Conservation of domains
Besides differences in subunits, protein domains are
conserved in many but not all cases. The subunit dAtac1
(Guelman et al. 2006a) lacks a C-terminal ZnF domain
that is present in human Atac1 (Wang et al. 2008; Guelman
et al. 2009; Nagy et al. 2010). Atac2 contains an active
HAT domain (see below), the fly homolog contains
a canonical PHD finger at the N terminus, and the human
homolog may harbor a different type of ZnF (Nagy et al.
2010). PHD fingers have been identified as binding
modules to methylated histone tails (Baker et al. 2008).
Hence, its absence in human Atac2 may affect the
chromatin-binding properties of ATAC. The Mbip sub-
unit shows distinct domain organization in flies and
humans. Fly Mbip/CG10238 contains two domains: an
N-terminal MoaE domain absent from the human protein,
and a C-terminal MBIP domain, which comprises the
entire human Mbip protein (Suganuma et al. 2010). Since
the MoaE domain has been shown to mediate interaction
between ATAC and MAPK signaling, its absence from
human Mbip may have functional consequences for the
interplay between ATAC and signal transduction path-
ways (Suganuma et al. 2010). Finally, human Yeats2
contains both YEATS and HF domains (Wang et al. 2008).
While several programs fail to detect a HF in Drosophila
Yeats2, alignments using ClustalW2 show strong conser-
vation of the HF sequence at residues 869–969.
Links with other protein complexes
ATAC has several links with related protein complexes
via shared subunits. The WD repeat proteins fly Wds or
human Wdr5 link ATAC to the Set1/MLL complexes in-
volved in methylation of histone H3 at Lys 4 (Shilatifard
2008). Inclusion of Hcf1 could also link functions of
ATAC to the MLL and/or the Sin3 HDAC complexes
(Wysocka et al. 2003). The Chrac14 subunit is a bona fide
HF-containing subunit of fly ATAC. Its human ortholog,
hChrac17, has been detected in some (Wang et al. 2008),
but not all (Guelman et al. 2009; Nagy et al. 2009), human
ATAC purifications. Chrac14/Chrac17 is also a subunit of
ISWI-containing ATP-dependent chromatin remodeling
complexes (Varga-Weisz et al. 1997; Poot et al. 2000),
which initiated functional studies on the role of ATAC
during chromatin remodeling (see below). An unexpected
HF-containing subunit of ATAC in both flies and humans
is Nc2b. This protein is conserved from yeast to humans
Structure and function of SAGA and ATAC
GENES & DEVELOPMENT531
and forms a stable heterodimeric complex with Nc2a.
This NC2 complex is a strong repressor of TBP-mediated
in vitro transcription (Kaiser and Meisterernst 1996;
Thomas and Chiang 2006). In yeast, the NC2 complex
associates with TBP, Mot1, and a small piece of inter-
nucleosomal DNA and is involved in regulating TBP
promoter association (van Werven et al. 2008). In flies,
NC2 is involved in core promoter selectivity (Hsu et al.
2008). The ATAC interaction partner for fly Nc2b is
Yeats2, and this heterodimer seems to plays a structural
role in ATAC (Wang et al. 2008).
Domains and structural comparison between ATAC
The domains presently identified in the SAGA and ATAC
subunits are indicated in Figure 1. Several known struc-
tural features of SAGA are shared with ATAC, but in
a variant form. These include HF-mediated heterodimer
pairs, a WD repeat protein, a HAT/chromatin interaction
module, and proteins required for structural integrity.
Strikingly different subunits decorate these structures.
In addition to the Yeats2/Nc2b interaction, several other
subunit interactions depend on HF motifs, which are
known to mediate protein dimerization (Gangloff et al.
2001). In SAGA, the following HF dimers are present:
between Taf9 (H3-like) and Taf6/Taf6L (H4-like), between
Ada1 (H2A-like) and Taf12 (H2B-like), and between Taf10
and Spt7 (Ogryzko et al. 1998; Wu and Winston 2002; Wu
et al. 2004; Koutelou et al. 2010). None of these subunits
are present in ATAC. However, some of these pairs are
(partially) shared with the basal transcription factor TFIID,
which harbors the HF pairs Taf6/Taf9, Taf4/Taf12, Taf3/
Taf10, Taf8/Taf10, and Taf11/Taf13 (Gangloff et al. 2001;
Cler et al. 2009). ATAC contains three HF proteins: Nc2b,
Yeats2,and Chrac14. WhileChrac14 andNc2b failtoform
heterodimers (Suganuma et al. 2008), HFs are required for
Yeats2/Nc2b interaction (Wang et al. 2008).
Another important structural feature of SAGA, ATAC,
and many other complexes, including TFIID, is the
presence of a WD repeat protein in a structural subunit,
which is involved in protein–protein interactions (Xu and
Min 2011). In SAGA and similarly in TFIID, this domain
is provided by Taf5/Wda/Taf5L. In ATAC, human Wdr5
and its fly ortholog, Wds, contain a WD repeat domain. It
is intriguing that exactly Wdr5 is shared with the H3K4
methyltransferase complex MLL (Wysocka et al. 2003),
which raises questions regarding the regulation of com-
plex assembly, the interplay between ATAC and MLL,
and the interaction with nucleosomes.
HAT/chromatin interaction module
The HAT/chromatin interaction module of SAGA and
ATAC is partially shared and specifies incorporation in
either complex. In SAGA, it consists of Gcn5/Pcaf, Ada3,
Sgf29, and Ada2b, and in ATAC, it consists of Gcn5/Pcaf,
Ada3, Sgf29, and Ada2a. Several domains in these pro-
teins are involved in chromatin recognition. For this
reason, we propose to name this the HAT/chromatin
interaction module. The first chromatin ‘‘reader’’ is pro-
vided by the bromodomain of Gcn5/Pcaf, which can bind
acetylated lysine residues on histones (Mujtaba et al.
2007). The second chromatin anchor has recently been
identified to be the Tudor domain of Sgf29, which can
bind trimethylated Lys 4 of histone H3 (H3K4me3) as-
sociated with transcription start sites (TSSs) (Barski et al.
2007; Vermeulen et al. 2010; Bian et al. 2011). Inter-
estingly, peptide pull-down experiments using H3K4me3-
modified peptides combined with quantitative mass spec-
trometry resulted in the specific binding of SAGA but not
ATAC subunits from HeLa cells, while Sgf29 is present in
both complexes (Vermeulen et al. 2010). It may therefore
be possible that the Tudor domain of Sgf29 preferentially
binds H3K4me3 when incorporated in SAGA but not
when in ATAC. Ada2a and Ada2b both contain three
domains involved in chromatin regulation: an N-terminal
domain (Muratoglu et al. 2003; Gamper et al. 2009). They
also contain conserved Ada boxes of unknown function
(Muratoglu et al. 2003). In vitro binding studies have in-
dicated that these domains are involved in contacting
Ada3 (via SWIRM) and Gcn5 (via ZnF and SANT) (Gamper
et al. 2009). The SWIRM domain of Ada2a can bind DNA
and potentiate chromatin remodeling induced by ACF
(Qian et al. 2005). It remains to be determined how the
and Ada3 cooperate to stimulate Gcn5-mediated histone
acetylation of nucleosomal templates but not of free
histones, which argues for a role of these proteins in chro-
matin interaction and/or allosteric control (Gamper et al.
2009). In addition to the HAT/chromatin interaction
module, several other domains are present in both SAGA
and ATAC that may mediate interactions with chroma-
tin. For SAGA, these include the bromodomain of yeast
Spt7 and the SCA7 domain of Sgf73. In ATAC, additional
potential chromatin anchors include the PHD finger of fly
Atac2, and the SANT and ZnF domains of Atac1. Atac2
also adds a second HAT activity to the ATAC complex
besides Gcn5 or Pcaf (see below).
SAGA, and Yeats2 (Wang et al. 2008) and Atac2 (Guelman
et al. 2009) in ATAC. As discussed above, the Wdr5/Wds
subunit could also serve an important role, but much less
is known about the structural core of ATAC at present.
In conclusion, SAGA and ATAC share a HAT/chroma-
tin interaction core with distinct properties dictated by
incorporation of Ada2b (stimulation of Gcn5 HAT activ-
ity) or Ada2a (no stimulation). Both complexes use a WD
repeat protein and distinct HF-mediated heterodimers.
Complex-specific subunits provide ample opportunities
for distinct ways of transcriptional regulation, including
Spedale et al.
532GENES & DEVELOPMENT
distinct enzymatic activities, additional chromatin in-
teraction motifs, distinct links with other chromatin
complexes, and subunits that link them to transcription
factors or signaling pathways.
Functional distinctions in chromatin modification
Several differences exist between SAGA and ATAC with
module specific for H2Bub (Powell et al. 2004; Ingvarsdottir
et al. 2005; Lee et al. 2005), which is absent from ATAC.
Several recent studies have shown that the DUB module
of metazoan SAGA, like in yeast, plays a role in the
regulationof a subsetof SAGA-dependent genes, including
c-Myc-responsive genes (Pijnappel and Timmers 2008;
Zhang et al. 2008; Zhao et al. 2008; Rodriguez-Navarro
2009; Weake et al. 2011). Second, ATAC contains two
HAT subunits, Gcn5/Pcaf and Atac2, and Ada2a instead
of Ada2b that differentially regulate the activity of Gcn5.
Results obtained using purified proteins and from in vivo
studies are described hereafter.
In vitro activities
Recombinant Atac2 protein displays HATactivity toward
both H3 and H4 when present as free histones, but the
activity is ;40-fold reduced compared with recombi-
nant Gcn5, which specifically acetylates H3 but not H4
(Guelman et al. 2009). Purified preparations of ATAC
have also been shown to possess HAT activity for both
H3 and H4, both as free histones and in nucleosomes
(Suganuma et al. 2008; Guelman et al. 2009; Nagy et al.
2010). Whereas SAGA and ATAC from flies both acety-
late H3 and H4 as free histones, SAGA showed strong
specificity for H3 and ATAC showed strong specificity for
H4 when nucleosomal substrates were used (Suganuma
et al. 2008). Altered substrate specificities may be dictated
by other complex subunits. In particular, Ada subunits can
affect the enzymatic activity of Gcn5 when tested on nu-
cleosomal substrates, and this property is conserved from
yeast to humans (Gamper et al. 2009). Interestingly, re-
combinant human Ada2b and Ada3 strongly stimulated
the HAT activity of Gcn5 toward mononucleosomes. Re-
placement of human Ada2b (SAGA-specific) with Ada2a
(ATAC-specific) abolished this stimulation. This suggests
that besides the presence of an additional HAT provided
by Atac2, ATAC may also possess a different HATactivity
caused by the diminished capacity of Ada2a to stimulate
In vivo activities
The contributions of ATAC to histone acetylation in vivo
have not been clarified yet. Both human and mouse
ATACs have been reported to be required for global
acetylation of H3K9, H4K5, H4K12, and H4K16, as shown
by knockdown of Atac2 in A549, HEK293 cells, and
mouse embryos (Guelman et al. 2009). Atac2 also ap-
peared to be required for complex integrity. No effects
were observed for acetylation of H3K14 and H4K8.
Another study reported that acetylation of H3K9 and
H3K14 was reduced by knockdown of the ATAC-specific
subunit Ada2a in HeLa cells and that H4K5, H4K12, and
H4K16 acetylation levels were unchanged (Nagy et al.
2010). In this study, the lack of effects on H4 acetylation
could be caused by the remaining Atac2 enzyme, which
would act either alone or in an ATAC-like subcomplex
lacking Ada2a. The consensus between these two studies
is represented only by H3K9. In flies, mutation of ATAC2
results in reduced global levels of H4K16ac. The un-
affected residues include H3K9, H3K14, H4K5, and
H4K8 (Suganuma et al. 2008). Another study reports
decreased global levels of H4K12ac in ADA2A mutant
flies (Ciurciu et al. 2008). This indicates partially similar
roles for Atac2 in the regulation of global acetylation
levels in flies and mammals: In both organisms, this HAT
is involved in the acetylation of H4K12 and H4K16. It
is important to realize that the above studies rely on
specificity and sensitivity of antibodies toward acetylated
histones. Application of quantitative mass spectrometry
to measure histone acetylation could resolve (some of)
Besides HAT activity toward the histone proteins,
a growing number of nonhistone substrates have been
identified for Gcn5 and Pcaf. Some of these (cyclin A,
ERRa, and Snf2) are discussed in more detail elsewhere in
this review. Additional examples include the Pcaf sub-
strates in mammals: p53 (Liu et al. 1999), HIF-1a (Xenaki
et al. 2008), b-catenin (Ge et al. 2009), c-myc (Patel et al.
2004), Pcaf autoacetylation (Blanco-Garcia et al. 2009),
and Cdk2 (Mateo et al. 2009). Nonhistone substrates for
Gcn5 include Cdc6 (Paolinelli et al. 2009), c-Myc (Patel
et al. 2004), ISWI in flies (Ferreira et al. 2007), and Rsc4 in
yeast (VanDemark et al. 2007). Besides histones, the Trf1
subunit of the shelterin complex is a substrate for the
DUB module of SAGA (Atanassov et al. 2009), and more
examples are likely to follow. In many cases, acetylation
and DUB has been shown to modulate the activity or
stability of these nonhistone substrates, and we refer to
several reviews for this (Sterner and Berger 2000; Yang
2004; Nagy and Tora 2007).
Interplay with signaling pathways
At present, six distinct types of (stress-induced) signaling
pathways have been described to involve SAGA-like
complexes: phorbol ester-induced (protein kinase C [PKC]),
UV-induced (p53), high osmotic stress-induced (MAPK),
sodium arsenite-induced (MAPK), thapsigargin-induced
(MAPK-ER stress), and nuclear receptor signaling (Fig. 3).
This indicates that SAGA and ATAC complexes in meta-
zoans play central roles in gene expression in response to
intracellular signaling. This property is conserved in
yeast, where SAGA was found to be most relevant for
stress-regulated genes (Huisinga and Pugh 2004).
Activation of the PKC pathway using the phorbol ester
TPA leads to induction of many genes, as observed by
staining Drosophila polytene chromosomes with anti-
Structure and function of SAGA and ATAC
GENES & DEVELOPMENT533
bodies against RNA polymerase II (pol II) (Nagy et al.
2010). Costaining with the ATAC-specific subunit Mbip/
CG10238 revealed a similar strong increase of its chro-
mosome association to sites of induced transcription. In
contrast, the SAGA-specific subunit Ada2b failed to show
TPA-induced chromosome association. As monitored by
its Atac1 and Atac2 subunits, human ATAC was recruited
to the TPA-induced genes cFOS, EGR1, and FRA1 and
was required for TPA-induced expression of these genes.
This effect was specific for ATAC, as SAGA was neither
recruited nor required for mRNA expression of these
genes (Nagy et al. 2010).
The tumor suppressor p53
Upon UV-induced DNA damage, p53 becomes stabilized
by phosphorylation and induces a G1/S arrest and a DNA
damage response to allow DNA repair. Previous studies
have indicated a role for Gcn5 in regulating p53-induced
gene expression. More recent work has assigned this role
to metazoan SAGA, rather than ATAC. In Drosophila
cells, Ada2b but not Ada2a protein interacts with p53.
ADA2B but not ADA2A showed genetic interaction with
p53 in affecting the pigment contents of adult eyes
(Pankotai et al. 2005). In human cells, the SAGA-specific
subunit Ada2b but not the ATAC-specific subunit Ada2a
was recruited to the p53 response genes CDKN1A/p21,
GADD45, and PUMA (Gamper et al. 2009). These find-
ings show that the preferential interaction between p53
and SAGA, rather than ATAC, has been conserved from
flies to humans.
Distinct MAPK pathways exist in yeast, flies, and
humans (Chen and Thorner 2007; Cuadrado and Nebreda
2010). These kinase cascades can be induced by signals
including peptide growth factors, hormones, and various
stresses, including starvation, oxidative stress, and high
osmolarity stress. Pathways include multiple MAPK
subfamilies, of which mammalian ERK, JNK, and p38
(Hog1 in yeast) have been most studied. Depending on the
stress signal and the specific MAPK pathway involved,
either SAGA or ATAC was shown to play an important
role in regulating stress-induced gene expression.
Stress induced by high osmolarity can be achieved using
high concentrations of sorbitol or NaCl in the medium
and involves SAGA in yeast and ATAC in flies. In yeast,
osmotic stress activates the Hog1 protein kinase, which
has a number of functions, including phosphorylation of
transcription factors and promoter recruitment of pol II.
For example, Hog1 phosphorylation switches Sko1 from
a repressor to an activator, which recruits yeast SAGA
stress response genes (Proft and Struhl 2002). Nadal and
coworkers (Zapater et al. 2007) used the osmotic stress
response gene STL1 as a model showing activation
by sequential promoter recruitment of Hog1, SAGA, and
the Mediator coactivator complex, respectively. Both
SAGA and Mediator appeared to be required for STL1
induction. In Drosophila cells, the first evidence for a role
of ATAC in MAPK signaling was obtained by proteomic
analysis: The ATAC subunit Mbip/CG10238 is known as
MUK (MAPK upstream kinase)-binding inhibitory pro-
tein, and several MAPK pathway components were iden-
tified as substoichiometric ATAC interactors (Suganuma
et al. 2010). Using activation of JNK (Jun kinase) by
phosphorylation in response to osmotic stress as a read-
out, Workman and coworkers (Suganuma et al. 2010)
found that overexpression of the Mbip/CG10238 subunit
of ATAC inhibited, while knockdown of ATAC subunits
(Atac2 or Nc2b) potentiated, JNK activation. Detailed
analysis of two JNK target genes, Jra/JNK itself (via
autoregulation) and Chickadee, revealed differential reg-
ulation by ATAC under basal and activated conditions.
Without osmotic stress induction, expression of these
genes was positively regulated by ATAC, which occurred
mostly via Atac2. In contrast, during osmotic stress
induction, ATAC functions to inhibit expression of these
genes, mostly via Mbip/CG10238. These results show
that the role of ATAC in osmotic stress gene regulation is
more complex than just the analogous SAGA function in
yeast. It would be interesting to know which factors
positively regulate osmotic stress-induced gene regula-
tion in Drosophila cells. Could this involve the SAGA
pathways. See the text for details.
Interplay between SAGA and ATAC with signaling
Spedale et al.
534 GENES & DEVELOPMENT
Sodium arsenite-induced signaling
Proteomic analysis also suggested a link between MAPK
signaling and human SAGA. Identification of human
Spt20 (Nagy et al. 2009) showed that this protein is
identical to p38IP, which was previously described as an
interactor of p38 MAPK (Zohn et al. 2006). The p38
MAPK pathway can be induced by sodium arsenite and
is distinct from the JNK pathway. Activation of p38
MAPK failed to induce recruitment of SAGA to the early
response gene EGR1, suggesting that SAGA may not play
a role during this type of stress (Nagy et al. 2009). EGR1 is
also induced upon PKC activation (see above) and re-
quires ATAC for induction. It would be interesting to
determine the involvement of SAGA and ATAC in stress-
induced gene expression on a genome-wide scale.
Endoplasmic reticulum (ER) stress pathways
Early studies from yeast have shown that SAGA is
involved in the unfolded protein response (UPR) follow-
ing ER stress (Welihinda et al. 2000). Deletion of the yeast
SAGA subunits GCN5, ADA2, or ADA3 prevented a
proper UPR. The requirement for SAGA during the ER
stress response has been conserved during evolution. In
human cells, induction of ER stress using thapsigargin
leads to the recruitment of the SAGA subunits Spt20,
Spt3, and Sgf11 to the ER stress-induced genes CHOP,
ERP70, HERPUD, and GRP78 (Nagy et al. 2009). Knock-
down of Spt20 and several DUB module subunits inhibits
ER stress induction of these genes, indicating that SAGA
recruitment is critical for gene induction (Nagy et al.
2009; Lang et al. 2011). In agreement, it has been reported
that human SAGA interacts with the NF-Y transcription
factor,which is involved in the ER response (Schroder and
Kaufman 2005). These findings indicate that SAGA in-
teracts with the ER stress pathway in both yeast and
humans. It is currently unknown whether ATAC can also
play a role during ER stress-induced gene expression.
Nuclear receptor (NR) signaling
Several NRs have been shown to use SAGA as a cofactor
to regulate transcription of their target genes. These
include RARa, RXR, ERa, PR, androgen receptor (AR),
and the orphan receptor ERRa. Several direct protein–
protein interactions between SAGA and NRs have been
reported. These include the Tra1 subunit that contains
three LXXLL motifs known to mediate binding to NRs
(Yanagisawa et al. 2002). Contacts between Ada3 and
RARa, RXR, and ERa have also been observed, which
may be mediated by the LXXLL motif of Ada3 (Zeng et al.
2002; Meng et al. 2004; Li et al. 2010). Besides promoting
gene expression via histone acetylation, SAGA also may
acetylate the NR itself, as is the case for ERRa (Wilson
et al. 2010). Acetylation of this NR by Pcaf reduces its
DNA-binding activity, resulting in repression of gene
expression. Interestingly, evidence indicates that the DUB
module of SAGA plays a role in AR-mediated trans-
activation in both Drosophila embryos and human cells
(Zhao et al. 2008).
An important aspect that has been mostly unexplored
is whether recruitment of SAGA-like complexes to
stress-regulated genes also results in direct regulation of
their activity by stress-regulated kinases. Upon activa-
tion, several kinases become recruited to target genes in
both yeast and human cells (Alepuz et al. 2001; Hu et al.
2009; Lawrence et al. 2009). We hypothesize that these
kinases could directly modify the in situ binding and/or
different biochemical activities of SAGA-like complexes
at target promoters. Large-scale proteomic surveys re-
vealed a large number of acetylations and phosphoryla-
tions of subunits of SAGA-like complexes (Supplemental
Table S1). It would be interesting to determine whether
these modifications are dynamic and/or alter the proper-
ties of SAGA-like complexes. Direct kinase-mediated
regulation of coactivator complexes would allow for very
dynamic and localized events during the activation or
desensitization of transcription.
Taken together, SAGA functions during p53 induction,
ER stress, and nuclear receptor signaling, while ATAC
plays a role during signaling by PKC and osmotic stress-
induced MAPK signaling. Some of these pathways have
early eukaryotic ancestors such as osmotic stress in-
duction via Hog1 and ER stress, both of which involve
regulation by yeast SAGA. This shows that SAGA-like
complexes have diversified during evolution to regulate
distinct signaling pathways.
Interplay with chromatin remodelers
and transcription coactivators
Previous work has suggested a connection between the
ATAC-specific subunit Ada2a and chromatin remodeling.
These include a physical interaction between human
Ada2a and SWI/SNF (Barlev et al. 2003), and the above-
mentioned potentiation of ACF-induced chromatin re-
modeling by the SWIRM domain of human Ada2a (Qian
et al. 2005). Recent proteomic links also provided evi-
dence for involvement of ATAC in chromatin remodeling.
These include the stable presence of Chrac14/Chrac17and
Nc2b in ATAC (see above) (Suganuma et al. 2008; Wang
et al. 2008). These findings initiated the studies described
ATAC purified from insect cells stimulated nucleo-
some sliding induced by several chromatin remodeling
complexes, including yeast ISWI, SWI/SNF, and RSC
(Suganuma et al. 2008). This effect appeared to be me-
diated by the action of Chrac14. Inclusion of acetyl-CoA
in the reaction further potentiated remodeling, which
suggests an involvement of acetylation. How acetylation
may influence remodeling is still unclear. Histone acet-
ylation could expose DNA for binding the remodeling
machines. However, a recent report describes an inhibi-
tory role for Gcn5-mediated acetylation of the catalytic
Snf2 subunit of the SWI/SNF complex, pointing to a more
complex mechanism (Kim et al. 2010). In vivo evidence
for interplay between ATAC and chromatin remodeling
was obtained from Drosophila. Overlapping sets of genes
were down-regulated in ADA2A mutant flies compared
with mutants for the NURF chromatin remodeling com-
Structure and function of SAGA and ATAC
GENES & DEVELOPMENT535
plex (Carre et al. 2008). Mutants of the catalytic subunit
of NURF, ISWI, showed strongly reduced Ada2a binding
to polytene chromosomes, suggesting that ISWI-medi-
ated remodeling is required for ATAC chromatin binding.
Thus, both in vitro and in vivo data point to interplay
between ATAC and chromatin remodeling machines.
Data so far suggest a mechanism in which chromatin
binding of ATAC depends on chromatin remodeling and
that the remodeling process can then be further modu-
lated by the action of the Chrac14 subunit of ATAC. How
this occurs at the molecular level should be addressed in
The Mediator complex represents an important inter-
mediary between gene-specific activators and pol II
(Thomas and Chiang 2006). Interestingly, ATAC but not
SAGA has been found to form stable interactions with
the Mediator complex in mammalian cells (Krebs et al.
2010). The interaction was observed only with the Gcn5
form of ATAC and was most strongly observed in plu-
ripotent embryonic stem cells. The Luzp1 protein is re-
sponsible for bridging Gcn5–ATAC with Mediator, and
these complexes are particularly important for transcrip-
tion of several noncoding RNA genes (Krebs et al. 2010).
Although several issues (e.g.,Luzp1–Gcn5interactionsand
Luzp1 interactions with SAGA) require further analyses,
these observations reveal another level of functional spe-
cialization between SAGA-like complexes in mammals.
Regulation of target gene expression during development
Several target genes have been described that are regu-
lated by either SAGA or ATAC. To investigate this on
a genome-wide scale, several studies now report both
overlapping and distinct sets of target genes in Drosophila
embryos and tissues and in human cells in culture. These
studies are described below.
Gene regulation in Drosophila
Larvae mutant for ADA2A (ATAC-specific), ADA2B
(SAGA-specific), or ADA3 (shared between ATAC and
SAGA) were analyzed using DNA microarrays (Carre
et al. 2008; Pankotai et al. 2010). Both SAGA and ATAC
appeared essential for embryonic development, but they
regulate different sets of genes, resulting in distinct phe-
notypes. Ablation of ATAC affected an order of a magni-
tude more genes compared with SAGA. These results are
consistent with the early lethal phenotype of ATAC
ablation occurring just after this stage and during meta-
morphosis. A master regulator of metamorphosis is the
ecdysone receptor. Gene expression profiles of ADA2A
mutants showed that 40% of all transcripts have changed
expression levels, many of which are part of the ecdysone
transcription pathway. In contrast, ADA2B mutants died
much later during development and affected only 3% of
transcripts when assayed at the larval stage, of which
many overlapped with ADA2A-regulated genes. Genes
affected by ADA2B mutations include those involved in
antimicrobial defense mechanisms (Zsindely et al. 2009).
However, mutations in the SAGA subunits ADA2B,
SGF11, and NONSTOP also affect genes in the ecdysone
pathway, suggesting that SAGA and ATAC have partially
additive or overlapping roles in this process (Weake et al.
2008). A function for the DUB module of SAGA was
found to regulate genes involved in photoreceptor axon
targeting (Weake et al. 2008). Direct target genes of SAGA
in Drosophila tissues have been identified using chroma-
tin immunoprecipitation (ChIP) and sequencing (ChIP-
seq) (Weake et al. 2011). Muscle cells or neuronal cells
were obtained from late stage Drosophila embryos by
GFP labeling and FACS sorting. ChIP-seq of the SAGA-
specific subunit Ada2b from these cells identified 1470
target genes in muscle, 59 genes in neurons, and 527
genes in both tissues. This suggests that SAGA regulates
many more genes in muscle compared with neuronal
cells. A subset of SAGA-binding sites in muscle colocal-
ized with known binding sites for the muscle-specific
transcription factor Mef2, suggesting that SAGA may
function as its coactivator. These intriguing results may
mean that either SAGA preferentially acts in certain
tissues or regulation by SAGA is linked to the prolifera-
tion status of the cells. The binding location of SAGA in
the Drosophila genome strongly correlated with that of
pol II. Both were mostly present at TSSs, but in 14% of
cases, they resided also within gene bodies. The location
of SAGA and pol II in gene bodies is in agreement with
previous suggestions that SAGA is involved in transcrip-
tional elongation (Henry et al. 2003). Current models
indicate that an elongation function for SAGA may be
mediated by the DUB module. Since this module is not
present in ATAC, the options for regulating gene expres-
sion differ significantly between SAGA and ATAC.
Gene regulation in mammals
In mice, both SAGA and ATAC are required for normal
embryonic development. Disruption of SAGA by knock-
out of p38IP (SPT20) resulted in gastrulation defects due
to a failure to down-regulate E-cadherin (Zohn et al.
2006). ATAC2 knockout mice display early embryonic
lethality due to cell cycle defects (Guelman et al. 2009).
The shared subunits GCN5 and PCAF showed differential
requirements for mouse development (Xu et al. 2000;
Yamauchi et al. 2000). Whereas PCAF disruption showed
no effect, it acted synergistically with GCN5 to induce an
earlier and more severe phenotype compared with loss of
GCN5 alone. This is explained by redundancy of PCAF
and GCN5 and the later developmental expression of
PCAF compared with GCN5. Interestingly, mice homo-
zygous for catalytically dead Gcn5 showed a less severe
phenotype with longer survival compared with a GCN5
deletion (Bu et al. 2007). This indicates that the HAT
activity does not account for all Gcn5/Pcaf functions,
which is concordant with studies in yeast and mammals
(Candau et al. 1997; Wang et al. 1997; Jiang et al. 1999).
Possibly, the Ada2 interaction domains and/or bromodo-
mains of Gcn5/Pcaf are relevant in this. The SAGA
subunit hAtxn7 (Sgf73) has been linked to the polyglut-
amine expansion disease SCA7, which is characterized by
cerebellum and brainstem neurodegeneration for poorly
Spedale et al.
536GENES & DEVELOPMENT
understood reasons (David et al. 1997; McCullough and
Grant 2010). The expanded glutamine repeat is located
prior to the first ZnF domain (Fig. 1) and changes protein
conformation, leading to aggregation and cellular toxic-
ity. Interestingly, the expanded protein still incorpo-
rates into the SAGA complex, which displays a reduced
HATactivity toward nucleosomes (McMahon et al. 2005;
Palhan et al. 2005). These results indicate that both
SAGA and ATAC play crucial roles during mammalian
development and cellular physiology.
Direct target genes of human ATAC have been com-
pared with those of SAGA by ChIP-seq analysis using
antibodies to the ATAC-specific subunit ZZZ3/Atac1
and the SAGA-specific subunit Spt20 (Krebs et al. 2011).
The results identified three gene categories in both hu-
man B-lymphoblasts and HeLa cells: those that bound
only SAGA, those that bound only ATAC, or those that
bound both. Binding profiles were then compared with
published profiles for marks of TSSs (H3K4me3 and pol II)
and enhancers (H3K4me1). The analysis indicated that
ATAC binds to three types of locations: at known en-
hancers, at TSSs, and at regions lacking either mark.
SAGA bound to two types of locations: known enhancers
(but ata lower amount of locations compared with ATAC)
and known TSSs. Gene ontology (GO) for both ATAC-
and SAGA-bound regions failed to show a preference
for binding either housekeeping or tissue-specific genes.
This contrasts with the situation in yeast, where SAGA
preferentially regulates stress-responsive genes, while
TFIID is important for housekeeping genes (Huisinga
and Pugh 2004). In metazoans, the role of SAGA-like
complexes has therefore expanded to regulate both clas-
ses of genes. Interestingly, a subset of the enhancers
bound by ATAC (but not by SAGA) lacked p300 binding.
Since p300 has been a canonical marker for enhancers,
this finding suggests the presence of a novel class of
enhancers marked by ATAC binding and lacking p300. It
would be interesting to investigate in what functional
aspects ATAC-specific enhancers differ from p300-marked
enhancers; e.g., do they have differentially acetylated
nucleosomes, and do they require specific interplay with
Taken together, these results show that SAGA and
ATAC regulate partially overlapping and partially distinct
sets of target genes. Remaining questions include the
following: How do the observed binding profiles change
upon distinct types of cellular stress, and for which of the
target genes is binding required for gene expression?
Regulation of cell cycle progression
Previous work has implicated yeast Gcn5 in progression
through the G2/M phase of the cell cycle (Howe et al.
2001). Recent work now shows that in metazoans, this
function has been conserved in ATAC, rather than in
SAGA. Knockdown of human Atac2 results in G2/M
accumulation (Guelman et al. 2009). ATAC2-null mice
die between embryonic days 8.5 and 11 due to a general
increase in apoptotic cells and G2/M arrest. Also, in
mouse NIH3T3 cells, knockdown of ATAC subunits
results in G2/M arrest, followed by mitotic abnormalities
(Orpinell et al. 2010). This effect is specific for ATAC,
since SAGA knockdown did not result in cell cycle
defects. The ATAC complex remains intact during mito-
sis and localizes to the mitotic spindle. A model for the
mechanism by which ATAC regulates cell cycle pro-
gression has been proposed (Orpinell et al. 2010). Via
one of its HATs, ATAC directly acetylates cyclin A,
which forms a complex with the Cdk2 kinase to regulate
early mitotic processes. Progression through mitosis re-
quires degradation of cyclin A, and this is promoted by
ATAC-mediated acetylation. A phosphorylation target of
cyclin A/Cdk2 is the Sirt2 HDAC, which is also required
for mitotic progression. Degradation of cyclin A leads to
an activating dephosphorylation of Sirt2. As a result, the
Sirt2 targets H4K16 and a-tubulin become deacetylated,
which triggers mitotic progression. This shows that
ATAC, while regulating transcription in interphase cells,
has an important, different role unrelated to transcription
during mitosis to modulate post-translational modifica-
tion of components of the cell cycle machinery. It would
be interesting to determine how the relocalization of
ATAC from chromatin to the mitotic spindle and back is
regulated and whether ATAC also regulates transcription
of cell cycle proteins.
Current knowledge establishes the multiplicity of SAGA-
like complexes in metazoans and defines distinct roles
for SAGA and ATAC. These are obvious at the level of
subunit composition, structural organization, enzymatic
activities, interplay with signaling pathways, regulation
of target gene expression, and cell cycle regulation. Al-
though much insight has been obtained, it is clear that
regulation by SAGA-like complexes is complex and that
many questions remain unanswered. What is the molec-
ular basis for the different activities of Gcn5 within
SAGA and ATAC? Why are certain complex subunits
shared with other protein complexes? What is the archi-
tectural organization of ATAC, and how is it recruited to
its genomic locations? What are the assembly routes for
SAGA and ATAC in cells? How do these complexes in-
teract with chromatin remodeling machines? Are the
activities of the SAGA-like complex subject to regulation
by post-translational modifications? Are there fundamen-
tal differences between SAGA and ATAC with respect to
the mechanism of gene regulation and with respect to
their specific chromatin writing and reading capacities?
We anticipate that in a few years time, significant progress
will be made in addressing these and related questions.
We thank Jacques Bonnet, Laszlo Tora, Andre ´e Schram, Maria
Koster, and members of the Timmers and Holstege groups for
discussion and suggestions. This work has been supported by the
Netherlands Genomics Initiative (Horizon Program no. 93516050),
the Netherlands Organization for Scientific Research (NWO-CW,
TOP no. 700.57.302), and the Netherlands Proteomics Centre.
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