73 The SW I/SNF complex contributes to the regulation of gene expression by altering the chromatin structure. Depending on the context, it can be involved in either transcriptional activation or repression. Growing genetic and molecular evidence indicate that subunits of the SW I/SNF complex act as tumor suppressors in human and mice. Results from biochemical and transfection studies suggest also that SW I/SNF participates either in the inhibition or activation of several oncogenes and tumor suppressor genes and/or control their transcriptional activity. These activities provide molecular insight into the mechanism underlying SW I/SNF function in tumor suppression. Addresses *Department of Cellular Biochemistry and Human Genetics, The Hebrew University–Hadassah Medical School, Ein Kerem, Jerusalem 91120, Israel; e-mail: agnesk@pob.huji.ac.il † Oncogenic Viruses Unit/URA1644 of the Centre National de la Recherche Scientifique, Department of Biotechnology, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France Correspondence: Agnès Klochendler-Yeivin Current Opinion in Genetics & Development 2002, 12:73–79 0959-437X/02/$ —see front matter © 2002 Elsevier Science Ltd. All rights reserved. Abbreviations BAF Brg1-associated factor CNS central nervous system dTCF Drosophila T-cell factor HDAC histone deacetylase ICM inner cell mass LOH loss of heterozygosity PBAF Polybromo- and Brg1-associated factors pRB retinoblastoma protein RSC remodels the structure of chromatin SWI/ SNF mating type switching/sucrose non-fermenting TSG tumor suppressor gene Introduction Histones serve a dual role in the nucleus of eukaryotic cells. First, they are assembled with DNA into nucleosomes that can form higher-order structures. Second, they establish a dynamic molecular interface and play an active role in the regulation of transcription. This regulation occurs at least in part by covalent modifications of the tails of core histones. Modifications such as acetylation, phosphorylation and methylation modulate the nucleosome structure and the interaction with activators and repressors. Furthermore, over the past few years, a growing number of studies have led to the identification of additional mechanisms that regulate chromatin function in conjunction with histone covalent modifications. These involve enzymatic complexes that remodel chromatin and serve as transcriptional co- factors (reviewed in [1]). One class of such co-factors is represented by the SWI/SNF remodeling complexes that alter the path of DNA around the nucleosomal histone core in an ATP-dependent manner, resulting in nucleosome mobilization (reviewed in [2]). First identified in the yeast Saccharomyces cerevisiae, SWI/SNF is a 2MDa multisubunit assembly that is highly conserved in eukaryotes. Mammalian SWI/SNF complexes contain one of the two potential catalytic ATPase subunits, Brm or Brg1. They further diverge biochemically in their subunit composition, suggesting that they might have specialized cellular functions [3]. Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression [4–6,7 • ]. The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. Genetic alterations or dysregulated expression of genes involved in cell-cycle control, differentiation, cell death or maintenance of genomic integrity may be sufficient to drive malignant transformation. The precise transcriptional response to cellular regulatory circuits involves the core transcription machinery, gene-specific activators or repressors, as well as chromatin-remodeling activities that may either antagonize or enhance the repressive effects of chromatin. It is not difficult to imagine that balanced chromatin remodeling activities are crucial to ensure accurate responses to developmental or environmental cues, and to prevent the transition of normal cells into cancer cells. In this review, we describe recent genetic studies supporting the idea that the SWI/SNF complex is involved in tumor suppression. We also discuss protein interactions and functions focusing on the regulatory pathways of tumor suppressors and oncogenes. Mutations in human primary tumors and tumor-derived cell lines Accumulating molecular genetic evidence suggests that ATP- dependent chromatin remodeling by the SWI/SNF complex plays a crucial role in human tumorigenesis. Bi-allelic deletions or truncating mutations of SNF5/INI1/BAF47 on chromosome 22q11 were shown to be associated with most cases of malignant rhabdoid tumor. This rare but very aggressive pediatric cancer was initially described in the kidney, and subsequently reported as occurring elsewhere, including liver, lung and CNS where it is termed atypical teratoid and rhabdoid tumor [8]. SNF5 mutations were also observed occurring at a high frequency in another early childhood neoplasm, choroid plexus carcinoma, as well as in some cases of medulloblastoma and cPNET (central primitive neuroectodermal tumor) [9]. Deletions of SNF5 have also been reported in chronic phase and blast crisis of chronic myeloid leukemia [10]. In addition to somatic alterations, constitutive mutations of SNF5 predispose to renal and extra-renal malignant SWI/ SNF chromatin remodeling and cancer Agnès Klochendler-Yeivin*, Christian Muchardt † and Moshe Yaniv †