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BRCA1 as a tumor suppressor linked to the regulation of epigenetic states: keeping oncomiRs under control
Olafur Stefansson, Manel Esteller
Breast Cancer Research , 2012, DOI: 10.1186/bcr3119
Abstract: Inherited mutations in BRCA1 greatly increase the risk of breast cancer [1]. Tumors arising in mutation carriers have generally lost the wild-type BRCA1 allele [2]. These findings have led to the definition of BRCA1 as a tumor suppressor. The BRCA1 gene has well-established roles in maintenance of genomic integrity, including DNA repair by homologous recombination, DNA decatenation, and regulation of centrosomes [3]. In accordance, extensive changes in chromosome structure and number are observed in tumors derived from carriers [4,5]. The tumor suppressor functions of BRCA1 are therefore commonly attributed to its role in genomic maintenance. The BRCA1 gene has other roles, however, including those related to cellular differentiation and transcriptional regulation.miRNAs are small noncoding RNAs (~22 nucleotides) that mediate post-transcriptional gene silencing by controlling the translation of mRNA into protein products [6]. In cancer, miRNAs are differentially expressed when compared with the corresponding normal tissue, and some have tumor suppressor properties whereas others are oncogenic (so-called oncomiRs) [7,8]. In a recent report, Chang and colleagues identified a novel role for BRCA1 as an important mediator of epigenetic repression of an oncomiR; that is, miRNA-155 [9].Change and colleagues report substantial differences in the ability of R1669Q, a BRCA1 mutation currently of unknown clinical significance (single amino-acid substitution), to rescue lethality of Brca1-null ES cells compared with wild-type BRCA1 [9]. The functional assays carried out suggest a significant role for the R1699Q mutation in tumor suppression. Nevertheless, R1699Q-expressing embryonic stem cells (Brca1 null) were not sensitive to DNA-damaging agents and did not show genomic instability. This finding is interesting, given the critical role carried out by BRCA1 gene products in the cellular response to DNA damage.Using microarrays, high expression of miRNA-155 was found in R1699Q
BRCA1 tumor suppressor network: focusing on its tail
Bin Wang
Cell & Bioscience , 2012, DOI: 10.1186/2045-3701-2-6
Abstract: Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer [1,2]. BRCA1 plays critical roles in a number of diverse cellular processes that ensure genome integrity and the increase risk of breast and ovarian cancer caused by mutation of BRCA1 has been attributed to increased genomic instability. To safeguard genome, cells have evolved a defensive mechanism, called the DNA damage response (DDR), to coordinate multiple cellular responses including DNA repair, cell cycle checkpoint regulation, transcription, senescence or apoptosis etc., to counteract genotoxic stress [3-6]. BRCA1 appears to act as a central mediator of the cellular response to DNA damage that regulates the activities of multiple repair and checkpoint pathways [3,5,7-10]. BRCA1 is a substrate of the central DNA damage response kinases ATM/ATR that control the DDR. It is required for homology directed repair, a pathway that facilitates error-free repair of double-strand breaks (DSBs) and resolution of stalled DNA replication forks through homologous recombination (HR) [9-11] as well as postreplicative repair in response to UV damage [12]. Recently it is suggested that much of BRCA1's role in maintaining genome stability is accounted for by its role in maintaining heterochromatin integrity via H2A ubiquitination [13].BRCA1 associates with multiple repair proteins and cell cycle regulators and such a capability to form multiple protein complexes contributes to its role in maintaining chromosome stability and tumor suppression (Figure 1). BRCA1 is a large protein of 1,863 amino acids. It contains two important domains at each end of the protein, a RING domain at the N-terminus and two BRCT domains at the C-terminus. Many clinically important mutations of BRCA1 gene frequently target these two domains. BRCA1 dimerizes with BARD1 through the RING domain present on each or the protein, forming an ubiquitin E3 ligase [14,15]. Earlier studies suggested that the
Methylation of the Tumor Suppressor Protein, BRCA1, Influences Its Transcriptional Cofactor Function  [PDF]
Irene Guendel,Lawrence Carpio,Caitlin Pedati,Arnold Schwartz,Christine Teal,Fatah Kashanchi,Kylene Kehn-Hall
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011379
Abstract: Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. This multifunctional nature of BRCA1 is achieved by exerting its many effects through modulation of transcription. Many cellular events are dictated by covalent modification of proteins, an important mechanism in regulating protein and genome function; of which protein methylation is an important posttranslational modification with activating or repressive effects.
Concerted Transcriptional Regulation by BRCA1 and COBRA1 in Breast Cancer Cells
Sarah E. Aiyar, HyungJun Cho, Jae Lee, Rong Li
International Journal of Biological Sciences , 2007,
Abstract: Cofactor of BRCA1 (COBRA1) was first identified as a protein that binds to the breast cancer susceptibility gene product BRCA1. COBRA1 modulates estrogen-dependent and independent transcription and suppresses the growth of breast cancer cells. Its expression is significantly reduced in metastatic and recurrent breast cancer, pointing to a tumor suppressor function in breast cancer development. In light of these initial implications of COBRA1 in human breast cancer, the current investigation sought to obtain more direct functional evidence that links COBRA1 with BRCA1 in transcriptional regulation in breast cancer cells. Small hairpin RNA (shRNA)-mediated gene knockdown and gene expression microarray were used to study the impact of COBRA1 and BRCA1 on global transcription in the same breast cancer cell background. The gene expression profiling study in tissue culture cells uncovers a significant overlap of COBRA1- and BRCA1-regulated genes, many of which have been previously implicated in breast cancer progression. The data shown herein support the notion that COBRA1 and BRCA1 may engage in common gene regulatory pathways to suppress breast cancer progression.
Analysis of the DNA Binding Activity of BRCA1 and Its Modulation by the Tumour Suppressor p53  [PDF]
Riffat Naseem, Michelle Webb
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002336
Abstract: Background The breast cancer susceptibility protein, BRCA1 functions to maintain the integrity of the genome. The exact mechanisms by which it does so, however, remain unclear. The ability of BRCA1 to bind directly to DNA suggests a more direct role. However, little research has been conducted to understand the functional relevance of this characteristic of BRCA1. In this study we examine the DNA substrate specificity of BRCA1 and how this may be controlled by one of its interacting partners, p53. Methodology/Principal Findings Using competition gel retardation assays we have examined the ability of residues 230-534 of BRCA1 to discriminate between different synthetic DNA substrates that mimic those recognised by the DNA damage response i.e. four-way junction DNA, mismatch containing DNA, bulge containing DNA and linear DNA. Of those tested the highest affinity observed was for four-way junction DNA, with a 20 fold excess of each of the other synthetic DNA's unable to compete for any of the bound BRCA1 230-534. We also observed a higher affinity for C:C and bulge containing DNA compared to linear duplex and G:T containing DNA. BRCA1 230-534 also has interaction sites for the tumour suppressor p53 and we show that titration of this complex into the DNA binding assays significantly reduces the affinity of BRCA1 for DNA. Conclusions/Significance In this paper we show that BRCA1 can discriminate between different types of DNA damage and we discuss the implications of this with respect to its function in DNA repair. We also show that the DNA binding activity can be inhibited by the tumour suppressor p53 and suggest that this may prevent genome destabilizing events such as HR between non-homologous sequences.
Distinct MicroRNA Subcellular Size and Expression Patterns in Human Cancer Cells  [PDF]
Beibei Chen,Bo Zhang,Huaxia Luo,Jiao Yuan,Geir Skogerb?,Runsheng Chen
International Journal of Cell Biology , 2012, DOI: 10.1155/2012/672462
Abstract: Introduction. Small noncoding RNAs have important regulatory functions in different cell pathways. It is believed that most of them mainly play role in gene post-transcriptional regulation in the cytoplasm. Recent evidence suggests miRNA and siRNA activity in the nucleus. Here, we show distinct genome-wide sub-cellular localization distribution profiles of small noncoding RNAs in human breast cancer cells. Methods. We separated breast cancer cell nuclei from cytoplasm, and identified small RNA sequences using a high-throughput sequencing platform. To determine the relationship between miRNA sub-cellular distribution and cancer progression, we used microarray analysis to examine the miRNA expression levels in nucleus and cytoplasm of three human cell lines, one normal breast cell line and two breast cancer cell lines. Logistic regression and SVM were used for further analysis. Results. The sub-cellular distribution of small noncoding RNAs shows that numerous miRNAs and their isoforms (isomiR) not only locate to the cytoplasm but also appeare in the nucleus. Subsequent microarray analyses indicated that the miRNA nuclear-cytoplasmic-ratio is a significant characteristic of different cancer cell lines. Conclusions. Our results indicate that the sub-cellular distribution is important for miRNA function, and that the characterization of the small RNAs sub-cellular localizome may contribute to cancer research and diagnosis. 1. Introduction Cancer is a syndrome with complex pathogeny and is one of the principal causes of mortality all over the world [1]. When a normal cell transforms to a tumor cell, a variety of genes change their expression characteristics. It is believed that the deregulation of oncogenes and tumor-suppressor-genes is one of the major causes of tumorigenesis. Present knowledge suggests that deregulation of gene expression consists of at least two aspects, abnormal gene expression levels and irregular localization of the gene products (i.e., mRNAs, proteins or noncoding RNAs). With the exception of a few reports concerned with the subcellular localization of the gene products of p53 and BRCA1 [2, 3], most focus has been on expression levels. Although recently an increasing number of noncoding RNA (ncRNA) (e.g., miR-21, miR-155, miR-122, and others) have been shown to act as oncogenes (oncomirs) or tumor-suppressor genes [4, 5], the sub-cellular localization of noncoding RNAs is not well known, and little effort have been directed at analyzing the sub-cellular localization regulation of microRNAs and other important noncoding RNAs [6]. Small
Structure-Function Of The Tumor Suppressor BRCA1  [cached]
Serena L. Clark,Ana M. Rodriguez,Russell R. Snyder,Gary D.V. Hankins
Computational and Structural Biotechnology Journal , 2012,
Abstract: BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons 11-13, and the BRCT domain. The BRCA1 RING domain mediates interactions between BRCA1 and other proteins and is responsible for the E3 ubiquitin ligase activity of BRCA1. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.
Analysis of loss of heterozygosity of the tumor suppressor genes p53 and BRCA1 in ovarial carcinomas  [PDF]
Petrovi? Bojana,Perovi? Milica,Novakovi? Ivana,Atanackovi? Jasmina
Vojnosanitetski Pregled , 2006, DOI: 10.2298/vsp0609813p
Abstract: Background/aim: Among the genes involved in ovarian carcinogenesis, there has been increased interest in tumor-suppressor genes p53 and BRCA1. Both of the genes make control of cell cycle, DNA repair and apoptosis. The p53 is a "genome guardian" inactivated in more than 50% of human cancers, while BRCA1 mutations are found mostly in breast and ovarian cancer. The aim of this investigation was to establish the frequency of loss of heterozygosity (LOH) in the regions of the genes p53 and BRCA1 in ovarian carcinomas, and to analyze the association of LOH with the disease stage and prognosis. Methods. We analyzed 20 patients with a confirmed diagnosis of epithelilal ovarian carcinoma. DNA for molecular-genetic analysis was extracted from the tumor tissue and blood as normal tissue of each person. Microsatellite markers of the regions of genes p53 and BRCA1 were amplified by PCR method. The determination of allelic status of microsatellites and detection of LOH was performed after PAA gel electroforesis. Results. Both of the analyzed microsatellite markers were informative in 13/20 (65%) cases. In the region of gene p53, LOH was established in 4/13 (30.7%) tumors. One of them had histological gradus G1, one had gradus G2, and two of them had gradus G3, while all were with the International Federation of Gynecology and Obstetrics (FIGO) IIIc stage. In the region of gene BRCA1, LOH was detected in 5/13 (38.5%) tumors. Four of them had histological gradus G2, and one had gradus G3, while by the (FIGO) classification one was with stage Ib, one was with stage IIIb, while the three were with stage IIIc. LOH in both of the analyzed regions was detected in one tumor (7.7%), with histological gradus G3 and the FIGO IIIc stage. Conclusion. The frequency of LOH in epthelial ovarian carcinomas was 30.7% and 38.5% for p53 and BRCA1 gene regions, respectively. Most of tumors with LOH had histological gradus G2 or G3, and the clinical FIGO stage IIIc, suggesting the association of this occurrence with a later phase of the disease.
Altered DNA Binding and Amplification of Human Breast Cancer Suppressor Gene BRCA1 Induced by a Novel Antitumor Compound, [Ru(η6-p-phenylethacrynate)Cl2(pta)]  [PDF]
Korawan Chakree,Chitchamai Ovatlarnporn,Paul J. Dyson,Adisorn Ratanaphan
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131013183
Abstract: The ruthenium-based complex [Ru(η 6- p-phenylethacrynate)Cl 2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the ethaRAPTA interaction with DNA, including probing the sequence specific modified DNA structural stability and DNA amplification using the breast cancer suppressor gene 1 ( BRCA1) of human breast and colon adenocarcinoma cell lines as models. The preference of ethaRAPTA base binding is in the order A > G > T > C. Once modified, the ethaRAPTA-induced BRCA1 structure has higher thermal stability than the modified equivalents of its related compound, RAPTA-C. EthaRAPTA exhibits a higher efficiency than RAPTA-C in inhibiting BRCA1 amplification. With respect to both compounds, the inhibition of BRCA1 amplification is more effective in an isolated system than in cell lines. These data provide evidence that will help to understand the process of elucidating the pathways involved in the response induced by ethaRAPTA.
BRCA1 as tumor suppressor: lord without its RING?
Andrew EH Elia, Stephen J Elledge
Breast Cancer Research , 2012, DOI: 10.1186/bcr3118
Abstract: Germline mutations in the BRCA1 and BRCA2 genes account for 5% of all breast cancers and nearly 80% of families with hereditary breast cancer and ovarian cancer. These genes preserve genomic integrity by playing important roles in multiple DNA damage response path-ways, including homologous recombination repair [1]. BRCA1 encodes a large 1,863-amino-acid protein that harbors an amino-terminal RING domain and two tandem carboxy-terminal BRCT domains (Figure 1a). The RING domain functions as an E3 ubiquitin ligase by recruiting an E2 ubiquitin-conjugating enzyme, while the BRCT domains are phosphopeptide recognition modules [2,3] that enable BRCA1 binding to phosphorylated partners such as Abraxas, BACH1, and CtIP [1]. Cancer-causing mutations in patients occur in both the RING and BRCT domains.BRCA1 is unlike most E3 ubiquitin ligases in that its activity is enhanced by dimerization with the RING domain of a second protein, BARD1. The RING domains of BRCA1 and BARD1 form a four-helix bundle. Of note, the E2 enzyme makes contacts with the RING domain of BRCA1 but not with that of BARD1 (Figure 1b) [4]. The mechanism by which BARD1 promotes BRCA1 ligase activity is therefore unclear but may involve stabilizing a conformation of BRCA1 optimal for E2 binding. Using elegant mouse models, two recent studies have examined the effect of missense RING mutations on the tumor suppression and DNA repair activities of BRCA1 [5,6].Shakya and colleagues generated mice expressing BRCA1 with the mutation I26A [5]. This mutation abrogates E2 binding (and thus ubiquitin-ligase activity) but allows assembly of the BRCA1/BARD1 heterodimer. Notably, the BRCA1 RING can directly bind at least eight E2 enzymes, all of which support mono-ubiquitination or poly-ubiquitination in vitro, and I26A mutation ablates interaction with each of these E2 enzymes [7]. Surprisingly, the authors found that the I26A mutation in mice prevented tumor formation to the same degree as wild-type BRCA1 in three co
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