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The Many Roles of BAF (Mswi/SNF) and PBAF Complexes in Cancer

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The Many Roles of BAF (Mswi/SNF) and PBAF Complexes in Cancer Downloaded from http://perspectivesinmedicine.cshlp.org/ at Cold Spring Harbor Laboratory Library on July 14, 2016 - Published by Cold Spring Harbor Laboratory Press The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer Courtney Hodges, Jacob G. Kirkland, and Gerald R. Crabtree Departments of Pathology, Developmental Biology, and Genetics, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305 Correspondence: [email protected] During the last decade, a host of epigenetic mechanisms were found to contribute to cancer and other human diseases. Several genomic studies have revealed that 20% of malignan- cies have alterations of the subunits of polymorphic BRG-/BRM-associated factor (BAF) and Polybromo-associated BAF (PBAF) complexes, making them among the most frequently mutated complexes in cancer. Recurrent mutations arise in genes encoding several BAF/ PBAF subunits, including ARID1A, ARID2, PBRM1, SMARCA4, and SMARCB1. These sub- units share some degree of conservation with subunits from related adenosine triphosphate (ATP)-dependent chromatin remodeling complexes in model organisms, in which a large body of work provides insight into their roles in cancer. Here, we review the roles of BAF- and PBAF-like complexes in these organisms, and relate these findings to recent discoveries in cancer epigenomics. We review several roles of BAF and PBAF complexes in cancer, includ- ing transcriptional regulation, DNA repair, and regulation of chromatin architecture and topology.More recent results highlight the need for new techniques to study these complexes. EPIGENOMICS IN CANCER the full spectrum of achievable cell-type diver- sity for the organism. Because epigenetic regu- roadly defined, epigenetic factors contrib- lation contributes to cell-type functional spe- Bute to the expression state of the genome cialization, it is essential for multicellular life. by regulating heritable changes in gene ex- An important component of the epigenetic www.perspectivesinmedicine.org pression independently of the DNA sequence. state is the regulation provided by adenosine Chromatin-based epigenetic regulation occurs triphosphate (ATP)-dependent chromatin re- through a wide variety of mechanisms, includ- modelers, which use ATP to physically remod- ing physical compaction and exclusion, recruit- el histones and other factors on chromatin. ment of transcription machinery, or covalent As we review below, genomic studies of pri- modification of DNA and histones. Such fea- mary tumors and cancer cell lines have revealed tures constitute the heritable physicochemical that ATP-dependent chromatin remodelers are state of the genetic material, and are jointly re- among the most frequently disrupted genes ferred to as the epigenetic landscape. The com- in cancer. Because several important compo- binatorial regulation of these features represents nents of ATP-dependent chromatin remodelers Editors: Scott A. Armstrong, Steven Henikoff, and Christopher R. Vakoc Additional Perspectives on Chromatin Deregulation in Cancer available at www.perspectivesinmedicine.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a026930 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ at Cold Spring Harbor Laboratory Library on July 14, 2016 - Published by Cold Spring Harbor Laboratory Press C. Hodges et al. are conserved between yeast, flies, and humans stability, or histone content of nucleosomes, (Fig. 1), the basic research on chromatin re- and is well described in other reviews (Becker modeling performed in model organisms is and Horz 2002; Narlikar et al. 2013). However, taking on new relevance for disease biology. In as we discuss below, SWI/SNF-like complexes many cases, fundamental observations from have rich and biologically diverse regulatory yeast and flies directly support our understand- roles in vivo that arise through mechanisms ing of the role of chromatin remodelers in can- that are not entirely clear. cer; in other cases, the differences between these In yeast, SWI/SNF is a 1.15-MDa pro- organisms and humans highlight important tein complex (Smith et al. 2003) composed of gaps in our knowledge of disease mechanisms. Swi1, Snf2, Swi3, Snf5, Snf6, along with Swp- In this review, we focus on the family of and actin-related proteins (ARPs) (Fig. 1). Most BRG-/BRM-associated factor ([BAF] or mSWI/ subunits of the complex, including the ATPase SNF) and Polybromo-associated BAF (PBAF) Snf2, are present as single copies in the complex, complexes, whose subunits have been identified whereas several others integrate in multiple cop- as major tumor suppressors in several malig- ies (two copies of Swi3, Swp82, Snf6, and Snf11, nancies (Davoli et al. 2013; Kadoch et al. 2013; and three copies of Swp29) (Smith et al. 2003). Shain and Pollack 2013). Here, we relate the Many of these subunits are required for the fundamental biology revealed by genetics, struc- complex’s biological activity and, in some cases, tural biology, and microscopy to the fast-mov- its biochemical stability (Estruch and Carlson ing field of cancer epigenomics. As we discuss 1990; Richmond and Peterson 1996). The com- below, the mechanisms revealed by fundamen- plex’s direct interaction with nucleosomal DNA tal studies inform our understanding of how is mediated by the catalytic subunit Snf2, where- epigenetic dysfunction contributes to cancer. as other subunits, such as Snf5, do not interact with nucleosomal DNA but instead contact the histone octamer (Dechassa et al. 2008). SWI/SNF AND RSC IN Saccharomyces Cells with SWI/SNF subunit mutations cerevisiae have disrupted chromatin structures, and fail to express many genes, leading to diverse phe- The SWI/SNF Complex notypic defects. As a result, several aspects of the ATP-dependent chromatin remodelers were in- complex’s biological activity are illustrated by dependently discovered in yeast, by screening genetic deletion of its subunits. for mutations that disrupt the ability of yeast Failure to activate gene expression affects to switch mating type (Stern et al. 1984) or several downstream processes. As an example, www.perspectivesinmedicine.org activate sucrose fermentation pathways (Carl- cells lacking the central ATPase Snf2 are viable son et al. 1981; Neigeborn and Carlson 1984, but have impaired mating-type switching 1987), both in response to extrinsic cues. Later because of the inability to express the HO en- work showed that many of these genes act in donuclease needed for the process. Proper ex- concert through a common complex that regu- pression of HO depends not only on Snf2, but lated transcription, termed SWI/SNF to honor also Snf1 and Swi3 (Stern et al. 1984). In addi- both discoveries (Peterson and Herskowitz tion to the effects on sucrose metabolism, snf2D 1992; Winston and Carlson 1992; Cairns et al. cells also have impaired sporulation. However, 1994; Peterson et al. 1994). The observation that SWI/SNF activity is not uniformly activating. histone mutants were able to reverse the pheno- Although Snf2 plays a role in activation of many typic defects associated with SWI/SNF muta- genes, it also is required for silencing of genes tion (Sternberg et al. 1987; Kruger et al. 1995) at rDNA and telomeric loci, either by direct or indicated that regulation of chromatin struc- indirect means (Dror and Winston 2004; Man- ture was the central function of the SWI/SNF ning and Peterson 2014). complex. In vitro, ATP-dependent remodeling SWI/SNF subunits also have important activity induces changes of position, phasing, functions in maintaining proper chromatin- 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a026930 Downloaded from http://perspectivesinmedicine.cshlp.org/ at Cold Spring Harbor Laboratory Library on July 14, 2016 - Published by Cold Spring Harbor Laboratory Press A BAF-like PBAF-like remodeling complexes remodeling complexes Mya (estimated) Rsc7 Rsc1/2 Rsc13 1500 750 0 Rsc15 or Swp82 Taf14 Snf11 Rsc10 Snf6 Rsc3 and 30 Rsc4 Rsc5 Swp29 Snf5 Rsc14 Sfh1 Swi1 Rsc9 Swp73 Rsc6 Swi2/ Sth1 Snf2 Arp7 Arp7 Budding yeast Swi3 Swi3 Arp9 Rsc8 Rsc8 Arp9 SWI/SNF complex RSC complex Saccharomyces cerevisiae Saccharomyces cerevisiae Poly- bromo SAYP SNR1 SNR1 OSA BAP170 BAP60 BRM BAP60 BRM β-Actin β-Actin Fruit fly MOR MOR BAP BAP55 MOR MOR BAP BAP55 111 111 BAP complex PBAP complex Drosophila melanogaster Drosophila melanogaster BRD9 BRD7 DPF PHF PBRM1 BCL11 1/2/3 (or SS18L1) BCL11 10 A/B SS18 BCL7 A/B BCL7 Mouse BAF BAF A/B/C A/B/C ARID1A/B 47 47 BAF60 BAF60 ARID2 A/B/C BRG/ A/B/C BRG BRM β-Actin β-Actin BAF BAF BAF BAF BAF53A/B BAF53A/B 155 170 BAF 155 170 BAF 57 57 Human 1500 750 0 BAF complexes PBAF complexes Mya (estimated) Homo sapiens, Mus musculus Homo sapiens, Mus musculus B HUGO symbol Alternative names HUGO symbol Alternative names ACTL6A/B BAF53A/B SMARCA2 BRM ARID1A/B BAF250A/B SMARCA4 BRG www.perspectivesinmedicine.org ARID2 BAF200 SMARCB1 BAF47, SNF5, INI1 BCL7A/B/C – SMARCC1/2 BAF155/BAF170 BCL11A/B – SMARCD1/2/3 BAF60A/B/C BRD7/9 – SMARCE1 BAF57 DPF1/2/3 BAF45B/D/CSS18 – PBRM1 BAF180, Polybromo SS18L1 CREST PHF10 BAF45A Figure 1. Homology between BAF and PBAF-like remodelers throughout evolution. (A) BAF and PBAF com- plexes in mammals share several features with Brahma-associated proteins (BAPs) and Polybromo-associated BAP (PBAP) complexes (Drosophila melanogaster), and SWI/SNF and RSC complexes (Saccharomyces cerevi- siae), respectively. The similarities and differences between these complexes throughout evolution provide insight into their biological regulation and their roles in cancer. BAF/PBAF subunits labeled in a boldface white font have important roles in malignancy. Time since species divergence was estimated using TimeTree (Hedges et al. 2006), and plotted as a function of time, millions of years ago (Mya). (B) Summary of BAF and PBAF subunits and alternative names used in the text. In some cases, abbreviated names rather than the official human genome organization (HUGO) symbols are used in the text because of space constraints.
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