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When the SWI/SNF Complex Remodels . . . the Cell Cycle

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When the SWI/SNF Complex Remodels . . . the Cell Cycle Oncogene (2001) 20, 3067 ± 3075 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc When the SWI/SNF complex remodels . the cell cycle Christian Muchardt*,1 and Moshe Yaniv1 1Unite des Virus OncogeÁnes, URA1644 du CNRS, DeÂpartement des Biotechnologies, Institut Pasteur, Paris, France Mammalian cells contain several chromatin-remodeling particle. The exact eect of this modi®cation is still complexes associated with the Brm and Brg1 helicase- unclear but it is likely that the loss of positive charges like proteins. These complexes likely represent the modify interactions between the histone tails and the functional homologs of the SWI/SNF and RSC DNA or the neighboring nucleosomes. The reaction complexes found in Saccharomyces cerevisiae. The can be reversed by histone deacetylases (HDACs) that mammalian chromatin-remodeling complexes are in- have a negative eect on transcriptional activity. The volved in both activation and repression of a variety of second category of factors that aect chromatin genes. Several lines of evidence also indicate that they encompasses protein complexes that use the energy of play a speci®c role in the regulation of cell growth. Brm ATP-hydrolysis to weaken the interaction between is down-regulated by ras signaling and its forced re- histone core particles and DNA. These complexes expression suppresses transformation by this oncogene. facilitate the binding of transcription factors to speci®c Besides, the Brg1 gene is silenced or mutated in several DNA sites and may thus mediate both activation and tumors cell lines and a Brg1-associated complex was repression, depending on the activity of the recruited recently found to co-purify with BRCA1, involved in transcriptional regulator. breast and ovarian cancers. Finally, the gene encoding SNF5/Ini1, a subunit common to all mammalian SWI/ SNF complexes, is inactivated in rhabdoid sarcomas, a SWI/SNF complexes in Saccharomyces cerevisiae very aggressive form of pediatric cancer. The current review will address observations made upon inactivation The prototype of the chromatin-remodeling complexes of Brm, Brg1 and SNF5/Ini1 by homologous recombina- is the SWI/SNF complex. This complex of 11 subunits tion in the mouse, as well as the possible implication of was initially characterized in S. cerevisiae through these factors in the regulation of the Retinoblastoma genetic and biochemical studies. Its chromatin-remo- pRb-mediated repression of the transcription factor E2F. deling activity relies on the SWI2/SNF2 subunit that Oncogene (2001) 20, 3067 ± 3075. contains a large helicase-like domain functioning as a DNA-dependent ATPase. Mutations in any of the swi/ Keywords: N-CoR; HDAC; Cyclin A; Cyclin E; G0 snf genes give rise to various phenotypes, including poor growth, the inability to use speci®c carbon sources and defects in mating type switching. However, these genes are not required for viability. Whole Introduction genome expression analysis has shown that the SWI/ SNF complex is required for normal expression of only Within the nucleus of an eucaryotic cell, DNA is 3 to 6% of all the S. cerevisiae genes, depending on the wrapped around the histone octamers composed of two study (Holstege et al., 1998; Sudarsanam et al., 2000). copies of each of the histones H2A, H2B, H3 and H4. About half of the genes aected more then threefold in These histone-DNA complexes known as the nucleo- swi/snf mutant strains are upregulated rather than somes form a potent obstacle for biological processes downregulated, indicating that the SWI/SNF complex requiring access to the DNA, like transcription, is also involved in transcriptional repression. It must replication or DNA repair. The cellular machineries also be noted that the genes regulated by SWI/SNF are allowing transcription factors to gain access to their scattered all over the genome, suggesting that the target promoters have been extensively studied in the complex aects chromatin structure locally rather than last decade. These machineries can be divided in two remodeling larger chromosomal domains (Sudarsanam categories: the histone acetylases and the chromatin et al., 2000). remodeling complexes. The histone acetylases or HATs S. cerevisiae expresses several other helicase-like add acetyl groups to the N-terminal tails of the proteins related to the catalytic subunit of the SWI/ histones that protrude out of the nucleosome core SNF complex. Among these proteins, Sth1p has the highest degree of homology with SWI2/SNF2 and it is associated with a large complex containing at least four other proteins homologous to SWI/SNF subunits *Correspondence: C Muchardt, Unite des Virus OncogeÁ nes, De partement des Biotechnologies, Institut Pasteur, 25, rue du (Table 1). In addition, this complex, known as RSC Docteur Roux, 75724 Paris Cedex 15, France (for Remodel the Structure of Chromatin) contains two Mammalian SWI/SNF and the cell cycle C Muchardt and M Yaniv 3068 Table 1 SWI/SNF-related complexes in yeast, Drosophila and human Yeast Drosophila Human SWI/SNF RSC BAP 1 BAF 2 PBAF 3 N-CoR 4 SWI2/SNF2 Sth1 5 Brahma 6 Brm or Brg1 7 Brg1 Brg1 SNF5 Sfh1 8 SNR1 9 hSNF5/INI1 10 hSNF5/INI1 hSNF5/INI1 SNF6 SNF11 SWI1 Osa 11 BAF250/p270 12 SWI3 RSC8 BAP155/Moira BAF170 and BAF155 BAF170 and BAF155 BAF170 and BAF155 SWP82 SWP73 RSC6 BAP60 BAF60a BAF60a SWP29/TFG-3/TAF30 SAS-5 Arp7 Arp7 BAP55 b-actin 13 b-actin Arp9 Arp9 BAP47/ACT1/ACT2 BAF53 BAF53 BAP111 BAF57 BAF57 Rsc1, Rsc2 and Rsc4 14 Polybromo/BAF180 15 TIF1b/KAP-1 HDAC3 1(Papoulas et al., 1998), 2(Kwon et al., 1994; Nie et al., 2000), 3(Kwon et al., 1994; Xue et al., 2000), 4(Underhill et al., 2000), 5(Du et al., 1998; Tsuchiya et al., 1998), 6(Tamkun et al., 1992), 7(Chiba et al., 1994; Khavari et al., 1993; Muchardt and Yaniv, 1993), 8(Cao et al., 1997), 9(Dingwall et al., 1995), 10(Kalpana et al., 1994; Muchardt et al., 1995), 11(Kal et al., 2000), 12(Nie et al., 2000), 13(Zhao et al., 1998), 14(Cairns et al., 1999), 15(Xue et al., 2000) actin-related subunits (Arp7p and Arp9p) also present dominant suppressors of Polycomb mutations (Tam- in the SWI/SNF complex. Several dierences exist kun et al., 1992). Subsequent biochemical studies however between the RSC and the SWI/SNF complex. showed that the protein is associated with a complex RSC is essential for growth and about 10-fold more very similar to the yeast SWI/SNF complex, containing abundant than the SWI/SNF complex. RSC function is at least six subunits related to SWI/SNF subunits required for normal cell cycle progression (Cao et al., (Dingwall et al., 1995; Papoulas et al., 1998). Another 1997; Du et al., 1998; Laurent et al., 1992) but the SWI2/SNF2-related protein, known as ISWI, has been involvement of the RSC complex in RNA Polymerase found associated with dierent chromatin remodeling II transcription has been somewhat controversial. complexes (Ito et al., 1997; Tsukiyama and Wu, 1995; Unlike most SWI/SNF proteins, RSC subunits do Varga-Weisz et al., 1995). However, it is clear that only not activate transcription when tethered to DNA the Brahma-associated (or BAP) complex has a through a heterologous DNA-binding domain (Sigrid composition and an activity closely related to yeast Schaper and Moshe Yaniv, unpublished observation). SWI/SNF (Kal et al., 2000). Besides, at non-permissive temperatures, a ts mutation In mammalian cells, the situation is far more in Sth1 induces alterations of centromeric chromatin complicated. These cells contain at least two proteins structure and perturbs chromosome segregation (Tsu- closely related to SWI2/SNF2, known as Brm and chiya et al., 1998). Other observations do however Brg1 (or SNF2a and SNF2b, respectively). In addition, connect the RSC complex with transcription. Some rsc biochemical studies have identi®ed dierent variants of mutations aect the expression of the CHA1 gene as the mammalian SWI/SNF complex that all contain well as certain genes involved in early meiosis (Moreira subunits related to several yeast SWI/SNF proteins and Holmberg, 1999; Yukawa et al., 1999). The RSC (Table 1). The SWI/SNF complexes elute in two complex also appears to cooperate with histone distinct fractions during puri®cation. The ®rst fraction acetylases. Indeed, the rsc1 and rsc2 genes code for contains two dierent complexes associated with either similar proteins and only mutation of both genes is Brm or Brg1, respectively. Because of their similar lethal. However a rsc1 or a rsc2 mutation, in biochemical properties, they are both referred to as the combination with mutations that impair the SAGA BAF or the SWI/SNF-A complex. They are character- histone acetylase complex, either cause lethality or ized by the presence of BAF250, a low speci®city strong mutant phenotypes. This clearly suggests a role DNA-binding subunit with homology to yeast SWI1 for the RSC complex in transcription regulation and Drosophila OSA. A subfraction of the BAF through chromatin remodeling (Cairns et al., 1999). complexes apparently also contains the tumor suppres- sor protein BRCA1 (Bochar et al., 2000). The second chromatographic fraction contains a complex called SWI/SNF complexes in higher eucaryotes PBAF or SWI/SNF-B. This complex is apparently associated only with Brg1 and not Brm. It also SWI/SNF proteins have been identi®ed in several contains the Polybromo protein that is not present in species other than yeast, including Arabidopsis, Droso- the BAF complex. Polybromo, also called BAF180, phila, C. elegans, Xenopus, chick, mouse and human. In contains six successive Bromodomains and shares some Drosophila, the closest relative of SWI2/SNF2 is homology with three subunits of the yeast RSC Brahma. It was initially isolated in a screen for complex, Rsc1, Rsc2 and Rsc4, both within and Oncogene Mammalian SWI/SNF and the cell cycle C Muchardt and M Yaniv 3069 ¯anking the Bromodomains (Cairns et al., 1999; up-regulation of the Brm gene (CM, unpublished Callebaut et al., 1999).
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