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TitleCorrecting errors in the BRCA1 warning system.
Journal, issue, pagesDNA Repair (Amst), Vol. 73, Page 120-128, Year 2019
Publish dateNov 22, 2018
AuthorsYanping Liang / William J Dearnaley / Nick A Alden / Maria J Solares / Brian L Gilmore / Kevin J Pridham / A Cameron Varano / Zhi Sheng / Elizabeth Alli / Deborah F Kelly /
PubMed AbstractGiven 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 ...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, BRCA1, 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 BRCA1, 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.
External linksDNA Repair (Amst) / PubMed:30503669 / PubMed Central
MethodsEM (single particle)
Resolution15.5 - 20.1 Å
Structure data

EMDB-8926:
Mutated p53-DNA assembly
Method: EM (single particle) / Resolution: 15.5 Å

EMDB-8927:
Wild-type p53-DNA assembly
Method: EM (single particle) / Resolution: 20.1 Å

Source
  • Homo sapiens (human)
  • Human (human)

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