# ATP-Dependent Chromatin Remodeling in Human Malignancy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $377,979

## Abstract

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.

## Key facts

- **NIH application ID:** 10169349
- **Project number:** 5R01CA163915-10
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Gerald R. Crabtree
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,979
- **Award type:** 5
- **Project period:** 2012-07-10 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169349

## Citation

> US National Institutes of Health, RePORTER application 10169349, ATP-Dependent Chromatin Remodeling in Human Malignancy (5R01CA163915-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10169349. Licensed CC0.

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