Correcting errors in the BRCA1 warning system

Yanping Liang, William J. Dearnaley, Nick A. Alden, Maria J. Solares, Brian L. Gilmore, Kevin J. Pridham, Cameron Varano, Zhi Sheng, Elizabeth Alli, Deb Kelly

Research output: Contribution to journalArticle

Abstract

Given its important role in human health and disease, remarkably little is known about the full-length three-dimensional (3D) molecular architecture of the breast cancer type 1 susceptibility protein (BRCA1), or its mechanisms to engage the tumor suppressor, TP53 (p53). Here, we show how a prevalent cancer-related mutation in the C-terminal region of the full-length protein, BRCA15382insC, affects its structural properties, yet can be biochemically corrected to restore its functional capacity. As a downstream consequence of restoring the ubiquitin ligase activity of mutated BRCA15382insC, the DNA repair response of p53 was enhanced in cellular extracts naturally deficient in BRCA1 protein expression. Complementary structural insights of p53 tetramers bound to DNA in different stage of the repair process support these biochemical findings in the context of human cancer cells. Equally important, we show how this knowledge can be used to lower the viability of breast cancer cells by modulating the stability of the BRCA1 protein and its associated players.

Original languageEnglish (US)
Pages (from-to)120-128
Number of pages9
JournalDNA Repair
Volume73
DOIs
StatePublished - Jan 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Liang, Y., Dearnaley, W. J., Alden, N. A., Solares, M. J., Gilmore, B. L., Pridham, K. J., Varano, C., Sheng, Z., Alli, E., & Kelly, D. (2019). Correcting errors in the BRCA1 warning system. DNA Repair, 73, 120-128. https://doi.org/10.1016/j.dnarep.2018.11.009