PubMed · 9255799
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G A Hawkins, L M Hoffman. 1997. Base excision sequence scanning.. https://doi.org/10.1038/nbt0897-803
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The tumor suppressor protein breast cancer type 1 susceptibility protein (BRCA1) plays a central role in maintaining genome stability through its involvement in DNA damage repair, transcriptional regulation, and cell-cycle control. BRCA1 functions as an obligate heterodimer with its binding partner, the BRCA1-associated RING domain protein 1 (BARD1), to coordinate accurate DNA repair. While the structured N- and C-terminal domains of BRCA1 have been well-characterized, the large central region encoded largely by exon 11 that comprises ~ 80% of the protein, is intrinsically disordered, and remains poorly structurally characterized. This intrinsically disordered region (IDR) harbors critical interaction interfaces for key proteins involved in genome maintenance, including RAD50, RAD51, MYC, and RB. Here, we report the backbone resonance assignments of a BRCA1 IDR construct spanning residues 467-696, providing a foundation for future studies aimed at understanding how the disordered central region of BRCA1 contributes to homologous recombination, interactions with BARD1, and overall BRCA1 tumor suppressor function.
Breast Cancer Gene 1 (BRCA1) is a critical regulator of genome integrity whose dysfunction greatly increases lifetime risk of breast and ovarian cancers. While BRCA1 has been extensively studied in the contexts of adult biology and cancer, its diverse functions, including homologous recombination-mediated DNA repair, cell cycle checkpoint activation, protein ubiquitination, and transcriptional regulation, have many underexplored implications. In early embryonic development, the maternal-to-zygotic transition (MZT) and subsequent developmental processes place extraordinary demands on DNA replication fidelity, cell cycle regulation, transcriptional activation, and chromatin remodeling. These critical processes overlap strikingly with canonical functions of BRCA1, yet its function in early development is poorly characterized. In this review, we investigate BRCA1 conservation across species and connect its well-established functions to findings from developmental studies to assess its role in development. We highlight evidence of BRCA1 mitigating genome integrity loss from diverse sources, maintaining the proliferative activity needed for successful germ layer formation and early tissue morphogenesis, and regulating transcription and epigenetic modifications. Together, this synthesis supports a model where BRCA1 acts as a multi-functional and dynamic regulator of early embryogenesis. Building on this, we propose outstanding questions that could further illuminate these developmental roles. Characterization of BRCA1 in early development may not only provide important insight into the origin and progression of cancer susceptibility but may also elucidate fundamental mechanisms shaping early development.
The breast and ovarian specific tumor suppressor protein, BRCA1, has been shown to be a transcription factor because its carboxyl terminus, when fused to the GAL4 DNA binding domain, activates gene expression in cells. In this study, purified GAL4-BRCA1 protein functions in transcriptional activation assays using a minimal in vitro system. When compared with a standard activator, GAL4-VP16, the levels of activation produced by the BRCA1 fusion protein were stronger when in the presence of certain coactivators. The transcriptional activation by BRCA1 is maximal when in the presence of the PC4 (positive component 4) coactivator but not HMG2 (high mobility group protein 2) and when the template is negatively supercoiled. By contrast, transcriptional activation by VP16 was highest in the presence of HMG2 as well as PC4 and when DNA templates had linear topology. Activation by VP16 was largely unaffected by the concentration of TFIIH, whereas activation by BRCA1 was strongly affected by TFIIH concentrations. The differing cofactor and template requirements suggest that GAL4-BRCA1 and GAL4-VP16 regulate different steps in the pathways that lead to transcriptional activation.