Reading the SETD2 Methyl Mark on Microtubules
Abstract
Background: According to the American Cancer Society annual report, there are more than 60,000 new cases of kidney cancer and more than 14,000 deaths from this disease every year in the United States. Chromatin remodelers are proteins that determine how DNA and its associated proteins (chromatin) are packaged, remodeled, and interpreted for the expression of genes. Genes encoding chromatin remodelers such as SETD2, PBRM1, and SMARCC1 are among the most frequently mutated, or otherwise inactivated, in kidney cancer. Our group has recently discovered that the chromatin remodeler SETD2 has two important functions in the cell, one of which we were already aware (chromatin remodeling) and a surprising new one remodeling the cytoskeleton by serving as a "writer" that places a mark on the cytoskeleton. The cytoskeleton maintains the shape and structure of the cell and controls key aspects of cancer biology, such as the integrity of the genome and cell movement, an important component of metastasis. Therefore, in order to fully understand and target chromatin remodeler defects in kidney cancer, we will need to focus on their effects on both chromatin and the cytoskeleton. Toward this goal, we must identify who "reads" (and how) the mark placed by SETD2 on the cytoskeleton. Both PBRM1 and SMARCC1 are candidate "readers" because they contain the type of molecular domains that would be expected to interact with the SETD2 mark. Hypothesis: We hypothesize that PBRM1 and/or SMARCC1 are the readers of the mark placed by SETD2 on the cytoskeleton. To test this concept and potentially identify other candidate "readers," we propose the following experiments: Use biochemical and genetic approaches to determine if PBRM1 and/or SMARCC1 recognize and bind to the SETD2 mark on the cytoskeleton. Perform an unbiased screening to determine if other proteins that are often mutated in kidney cancer contain molecular domains that can recognize and interact with the SETD2 mark on the cytoskeleton. Identify the exact areas within these proteins that are necessary and sufficient to specifically recognize the SETD2 mark on the cytoskeleton. Innovation: The effect of chromatin remodelers on the cytoskeleton is poorly understood. The proposed project will address the innovative hypothesis that these genes have a dual role on both chromatin and the cytoskeleton. In addition, from a technical standpoint, we will use an innovative, unbiased approach taking advantage of protein-domain microarray technology to screen for candidate "readers" of the SETD2 mark on the cytoskeleton. Impact: This project will generate crucial data, which would otherwise be lacking, that can guide future efforts to develop targeted therapies for kidney cancer. Even if our hypothesis is incorrect, the proposed experiments will provide valuable information on how defects in chromatin remodeler genes found in kidney cancer can affect the biology of cancer cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810543
Entities
People
- Durga Tripathi
Organizations
- Baylor College of Medicine
- United States Army