Abstract
BackgroundThe breast and ovarian cancer susceptibility gene BRCA1 encodes a multifunctional tumor suppressor protein BRCA1, which is involved in regulating cellular processes such as cell cycle, transcription, DNA repair, DNA damage response and chromatin remodeling. BRCA1 protein, located primarily in cell nuclei, interacts with multiple proteins and various DNA targets. It has been demonstrated that BRCA1 protein binds to damaged DNA and plays a role in the transcriptional regulation of downstream target genes. As a key protein in the repair of DNA double-strand breaks, the BRCA1-DNA binding properties, however, have not been reported in detail.ResultsIn this study, we provided detailed analyses of BRCA1 protein (DNA-binding domain, amino acid residues 444–1057) binding to topologically constrained non-B DNA structures (e.g. cruciform, triplex and quadruplex). Using electrophoretic retardation assay, atomic force microscopy and DNA binding competition assay, we showed the greatest preference of the BRCA1 DNA-binding domain to cruciform structure, followed by DNA quadruplex, with the weakest affinity to double stranded B-DNA and single stranded DNA. While preference of the BRCA1 protein to cruciform structures has been reported previously, our observations demonstrated for the first time a preferential binding of the BRCA1 protein also to triplex and quadruplex DNAs, including its visualization by atomic force microscopy.ConclusionsOur discovery highlights a direct BRCA1 protein interaction with DNA. When compared to double stranded DNA, such a strong preference of the BRCA1 protein to cruciform and quadruplex structures suggests its importance in biology and may thus shed insight into the role of these interactions in cell regulation and maintenance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12867-016-0068-6) contains supplementary material, which is available to authorized users.
Highlights
The breast and ovarian cancer susceptibility gene breast cancer-associated protein-1 (BRCA1) encodes a multifunctional tumor suppressor protein BRCA1, which is involved in regulating cellular processes such as cell cycle, transcription, DNA repair, DNA damage response and chromatin remodeling
Magnetic beads immunoprecipitation and atomic force microscopy (AFM), we demonstrated a strong preference of the central region of the BRCA1 protein to non-B DNA structures, especially to cruciform and quadruplex DNA structures
BRCA1‐L protein binds to different DNA targets We analyzed the central region of BRCA1 protein binding to different DNA targets in detail
Summary
The breast and ovarian cancer susceptibility gene BRCA1 encodes a multifunctional tumor suppressor protein BRCA1, which is involved in regulating cellular processes such as cell cycle, transcription, DNA repair, DNA damage response and chromatin remodeling. The BRCA1 protein is encoded by the tumor suppressor gene BRCA1, mutation in which occurs often in breast and ovarian cancer patients [1] This multifunctional protein plays critical roles in different cellular pathways including cell cycle, transcription, DNA repair, DNA damage response and chromatin remodeling [2,3,4]. Local nucleotide sequence-dependent conformational changes, which give rise to cruciform, left-handed DNA, triplex and quadruplex structures, could all be stabilized further by negative supercoiling [11,12,13] These non-B DNA structures can be recognized and stabilized by various proteins, resulting in modulation of transcription [14], replication [15], junction resolving [16] and chromatin remodeling [17]. The prevalence of G-quadruplexes in promoter regions and telomeres further reveals the significance of such structures in the genome
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