Mikaela Stewart, Ph.D.

The Stewart Lab uses biochemistry and structural biology techniques to better understand how protein structures relate to protein functions. Current projects are focused on the tumor suppressor protein, BRCA1. Some types of inherited mutations in BRCA1 are associated with increased risk of breast and ovarian cancer, but there are many reported BRCA1 mutations with unknown risk factors. To better predict the risk associated with these genetic variants, we are taking two approaches:

1) Study the effect of cancer associated variations and phosphorylation on the function of the unstructured central region.

While much is known about the structure and function of the BRCA1 N- and C-terminal domains, 80% of the protein made by the BRCA1 gene is in the central region between these two well studied domains.  We know that this region is important for BRCA1’s interactions with other proteins in the cell to accomplish DNA damage signaling, DNA damage repair, and cell cycle checkpoint signaling. Without knowing the molecular details of the BRCA1 central region interactions, it is difficult to predict the risk associated with the many variants of unknown significance in this region. We will establish which parts of this region are important for the various BRCA1 interactions to aid in genetic counseling.

2) Investigate the biochemical and structural similarities of the C. elegans BRCA1 homolog.

The model organism C. elegans contains a gene that is homologous to BRCA1 and functions in the DNA damage response and cell cycle checkpoint.  Establishing the biochemical and structural similarities of the C. elegans BRCA1 will allow us to use this model organism to better predict the risk associated with patient mutations.

Baker CNS, Pajela PGC, Martin DE, Dzyuba SV, Stewart MD. Proline variants in the BRCA1 coiled-coil domain disrupt folding and binding to PALB2. Protein Science. 34 (1): e5240. https://doi.org/10.1002/pro.5240 (2025) 

Claton LE, Baker C, Martin H, Dzyuba SV, Zaman K, Prokai L, Stewart MD, Simanek EE. Installation of an Indole on the BRCA1 Disordered Domain Using Triazine Chemistry. Biomolecules, 14(12), 1625. https://doi.org/10.3390/biom14121625 (2024) 

Thapa I, Sellin Jeffries MK, Stewart MD (2024). One of these strains is not like the others: C. elegans DW102 has an altered dependence on brc-1 and brd-1 for regulation of cyp gene transcription. microPublication Biology. 10.17912/micropub.biology.001152 (2024) 

Thapa I, Vahrenkamp R, Witus SR, Lightle C, Falkenberg O, Sellin Jeffries MK, Klevit RE, Stewart MD. Conservation of transcriptional regulation by BRCA1 and BARD1 in Caenorhabditis elegans. Nucleic Acids Research. 51 (5): 2108–2116 (2023). 

Witus SR, Stewart MD, Klevit RE. The BRCA1/BARD1 Ubiquitin Ligase and its Substrates. Biochemical Journal. 478 (18): 3467-3483 (2021). 

Witus SR, Burrell AL, Farrell DP, Kang J, Wang M, Hansen JM, Pravat A, Tuttle LM, Stewart MD, Brzovic PS, Chatterjee C, Zhao W, DiMaio F, Kollman JM, Klevit RE. BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1. Nature Structural & Molecular Biology. 28, 268–277 (2021).

The Stewart Lab has presented at national and international meetings of the Protein Society, American Society of Human Genetics, American Chemical Society, and Federation of American Societies for Experimental Biology. We also participate and present at regional conferences for the American Society of Biochemistry and Molecular Biology, Texas Genetic Society, and the Texas Protein Folding and Function Meeting.

 

• NIH R15 Grant. Disrupting Protein-Protein Interactions with Self-Assembling Macrocycles. (09/2023 - 08/2026)
• National Institutes of Health - Disrupting Protein-Protein Interactions with Self-Assembling Macrocycles. (09/2019 - 08/2022)
• TCU Research and Creative Activities Fund - Investigating tumor-suppressing protein interactions between BRCA1 and p53. (06/2019 - 05/2020)
• TCU Research and Creative Activities Fund. Investigating tumor-suppressing protein interactions between BRCA1 and PALB2. (06/2018 – 05/2019)

https://stewartlabblog.wordpress.com/