Strong preference of BRCA1 protein to topologically constrained non-B DNA structures

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Abstract

Background

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. 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.

Results

In 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.

Conclusions

Our 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 material

The online version of this article (doi:10.1186/s12867-016-0068-6) contains supplementary material, which is available to authorized users.

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Most cited references 43

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Four-stranded nucleic acids: structure, function and targeting of G-quadruplexes.

Julian Leon Huppert (2008)

There are many structures that can be adopted by nucleic acids other than the famous Watson-Crick duplex form. This tutorial review describes the guanine rich G-quadruplex structure, highlighting the chemical interactions governing its formation, and the topological variants that exist. The methods that are used to study G-quadruplex structures are described, with examples of the information that may be derived from these different methods. Next, the proposed biological functions of G-quadruplexes are discussed, highlighting especially their presence in telomeric regions and gene promoters. G-quadruplex structures are the subject of considerable interest for the development of small-molecule ligands, and are also the targets of a wide variety of natural proteins.

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DNA and RNA Quadruplex-Binding Proteins

Václav Brázda, Lucia Hároníková, Jack C. C. Liao … (2014)

Four-stranded DNA structures were structurally characterized in vitro by NMR, X-ray and Circular Dichroism spectroscopy in detail. Among the different types of quadruplexes (i-Motifs, minor groove quadruplexes, G-quadruplexes, etc.), the best described are G-quadruplexes which are featured by Hoogsteen base-paring. Sequences with the potential to form quadruplexes are widely present in genome of all organisms. They are found often in repetitive sequences such as telomeric ones, and also in promoter regions and 5' non-coding sequences. Recently, many proteins with binding affinity to G-quadruplexes have been identified. One of the initially portrayed G-rich regions, the human telomeric sequence (TTAGGG) n , is recognized by many proteins which can modulate telomerase activity. Sequences with the potential to form G-quadruplexes are often located in promoter regions of various oncogenes. The NHE III1 region of the c-MYC promoter has been shown to interact with nucleolin protein as well as other G-quadruplex-binding proteins. A number of G-rich sequences are also present in promoter region of estrogen receptor alpha. In addition to DNA quadruplexes, RNA quadruplexes, which are critical in translational regulation, have also been predicted and observed. For example, the RNA quadruplex formation in telomere-repeat-containing RNA is involved in interaction with TRF2 (telomere repeat binding factor 2) and plays key role in telomere regulation. All these fundamental examples suggest the importance of quadruplex structures in cell processes and their understanding may provide better insight into aging and disease development.

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Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae

Steve G. Hershman, Qijun Chen, Julia Lee … (2008)

Although well studied in vitro, the in vivo functions of G-quadruplexes (G4-DNA and G4-RNA) are only beginning to be defined. Recent studies have demonstrated enrichment for sequences with intramolecular G-quadruplex forming potential (QFP) in transcriptional promoters of humans, chickens and bacteria. Here we survey the yeast genome for QFP sequences and similarly find strong enrichment for these sequences in upstream promoter regions, as well as weaker but significant enrichment in open reading frames (ORFs). Further, four findings are consistent with roles for QFP sequences in transcriptional regulation. First, QFP is correlated with upstream promoter regions with low histone occupancy. Second, treatment of cells with N-methyl mesoporphyrin IX (NMM), which binds G-quadruplexes selectively in vitro, causes significant upregulation of loci with QFP-possessing promoters or ORFs. NMM also causes downregulation of loci connected with the function of the ribosomal DNA (rDNA), which itself has high QFP. Third, ORFs with QFP are selectively downregulated in sgs1 mutants that lack the G4-DNA-unwinding helicase Sgs1p. Fourth, a screen for yeast mutants that enhance or suppress growth inhibition by NMM revealed enrichment for chromatin and transcriptional regulators, as well as telomere maintenance factors. These findings raise the possibility that QFP sequences form bona fide G-quadruplexes in vivo and thus regulate transcription.

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Author and article information

Contributors

Václav Brázda: 420 541517231 , vaclav@ibp.cz

Lucia Hároníková: luh@ibp.cz

Jack C. C. Liao: jack.liao@uqconnect.edu.au

Helena Fridrichová: Helena.Fridrichova@seznam.cz

Eva B. Jagelská: evajag@ibp.cz

Journal

Journal ID (nlm-ta): BMC Mol Biol

Journal ID (iso-abbrev): BMC Mol. Biol

Title: BMC Molecular Biology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2199

Publication date (Electronic): 8 June 2016

Publication date PMC-release: 8 June 2016

Publication date Collection: 2016

Volume: 17

Electronic Location Identifier: 14

Affiliations

[ ]Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic

[ ]School of Medicine, University of Queensland, Brisbane, 4006 Australia

Article

Publisher ID: 68

DOI: 10.1186/s12867-016-0068-6

PMC ID: 4898351

PubMed ID: 27277344

SO-VID: ed6d00b3-e0b6-4c29-b548-2d6565cee708

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 August 2015

Date accepted : 30 May 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001824, Czech Science Foundation (CZ);

Award ID: 15-21855S

Award Recipient : Václav Brázda

Custom metadata

ScienceOpen disciplines: Molecular biology

Keywords: brca1 protein,dna binding,protein-dna complex

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ScienceOpen disciplines: Molecular biology

Keywords: brca1 protein, dna binding, protein-dna complex

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Strong preference of BRCA1 protein to topologically constrained non-B DNA structures

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Abstract

Background

Results

Conclusions

Electronic supplementary material

Related collections

Higher order chromatin architecture

Most cited references 43

Four-stranded nucleic acids: structure, function and targeting of G-quadruplexes.

DNA and RNA Quadruplex-Binding Proteins

Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae

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Cited by 6

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