ATP-Dependent Chromatin Remodeling in Human Malignancy

人类恶性肿瘤中 ATP 依赖性染色质重塑

• 批准号: 9900916
• 负责人: Gerald R. Crabtree
• 金额: $ 21.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900916
• 关键词: ATPase Domain; Amino Acids; Binding; Biological; Biological Assay; Characteristics; Chromatin; Complex; Dependence; Development; Gene Deletion; Genes; Genetic Recombination; Genetic Transcription; Genetic study; Genome; Grant; Human; Human Genetics; Investigation; Kinetics; Laboratories; Malignant Neoplasms; Mediating; Missense Mutation; Molecular; Mutation; Nature; Normal Cell; Oncogenic; PRC1 Protein; Pattern; Pharmaceutical Preparations; Play; Polycomb; Production; Proteins; Recurrence; Repression; Role; Specificity; Surface; System; Techniques; Therapeutic; Tumor Suppressor Proteins; Work; base; cancer cell; chromatin remodeling; combinatorial; design; early screening; exome sequencing; in vivo; inhibitor/antagonist; novel; repaired; small molecule; tool; tumor; tumorigenesis

ABSTRACT 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.

摘要