Recent exome sequencing studies have found that over 20% of human cancers have deleterious mutations in the genes encoding the subunits of mSWI/SNF (BAF) complexes. A much larger number of tumors have amplifications or deletions of these genes. These complexes are polymorphic assemblies of 15 subunits encoded by 28 genes giving rise to remarkable combinatorial specificity. This biologic specificity is reflected in the highly selective pattern of oncogenic mutations in specific subunits in specific cancers. Cancer mutations generally have the characteristics of tumor suppressors and are generally heterozygous, implying that they play a genetically dominant role in suppressing tumor formation. Work in our lab and others has led to the conclusion that the ability of these complexes to oppose polycomb-mediated repression contributes to their roles in both development and oncogenesis. Hence, we will focus our work on the mechanisms underlying the opposition between BAF and polycomb and its therapeutic consequences. First we will use a novel, newly designed in vivo chromatin remodeling assay to fully characterize the nature of the opposition on a minute-by- minute basis. Secondly, we will define the energetic requirements for BAF-polycomb opposition and the essential role of ATP in regulating binding and release of PRC1 from BAF. Third, we will fully characterize the direct interaction between BAF and polycomb repressive complex 1 (PRC1) in terms of subunits and domains that are essential for this interaction. Fourth, we will explore the consequences of disruption of BAF-polycomb opposition for repair, recombination and transcription over the genome. Finally, we will define the therapeutic potential of a group of small molecule BAF inhibitors that we identified in earlier screens. At the conclusion of these studies we should have a mechanistic understanding of BAF-polycomb opposition and have explored at least two potential paths for the production of cancer-specific drugs.

Public Health Relevance

Human genetic studies over the past 5 years revealed that mutations in the mSWI/SNF or BAF complex contribute to about 20% of human cancers. We will define the molecular mechanism by which the BAF or mSWI/SNF complex suppresses the emergence of cancer in humans and explore the possibility that small molecules binding to these complexes could be useful in treatment of specific kinds of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA163915-06
Application #
9238289
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Witkin, Keren L
Project Start
2012-07-10
Project End
2022-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Stanton, Benjamin Z; Chory, Emma J; Crabtree, Gerald R (2018) Chemically induced proximity in biology and medicine. Science 359:
Koh, Andrew S; Miller, Erik L; Buenrostro, Jason D et al. (2018) Rapid chromatin repression by Aire provides precise control of immune tolerance. Nat Immunol 19:162-172
Hodges, H Courtney; Stanton, Benjamin Z; Cermakova, Katerina et al. (2018) Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 25:61-72
Miller, Erik L; Hargreaves, Diana C; Kadoch, Cigall et al. (2017) TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol 24:344-352
Kadoch, Cigall; Williams, Robert T; Calarco, Joseph P et al. (2017) Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 49:213-222
Stanton, Benjamin Z; Hodges, Courtney; Calarco, Joseph P et al. (2017) Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet 49:282-288
Stanton, Benjamin Z; Hodges, Courtney; Crabtree, Gerald R et al. (2017) A General Non-Radioactive ATPase Assay for Chromatin Remodeling Complexes. Curr Protoc Chem Biol 9:1-10
Hodges, Courtney; Kirkland, Jacob G; Crabtree, Gerald R (2016) The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer. Cold Spring Harb Perspect Med 6:
Buscarlet, Manuel; Krasteva, Veneta; Ho, Lena et al. (2014) Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance. Blood 123:1720-8
Takebayashi, Shin-Ichiro; Lei, Ienglam; Ryba, Tyrone et al. (2013) Murine esBAF chromatin remodeling complex subunits BAF250a and Brg1 are necessary to maintain and reprogram pluripotency-specific replication timing of select replication domains. Epigenetics Chromatin 6:42

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