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BRCT phosphoprotein recognition, but not E3 ligase activity, is essential for BRCA1 tumor suppression

ABSTRACT: It has been recognized that BRCA1, in the form of the BRCA1/BARD1 heterodimer, acting as an ubiquitin E3 ligase offered a possible mechanism to explain its pleiotrophic nature of BRCA1 activity. Our observation that mice lacking BRCA1 enzymatic activity are viable apart from male sterility was unexpected. Our results suggest that the E3 ligase activity of BRCA1 is largely dispensable for normal development and is not essential for all BRCA1 functions. Thus, many of the known and unknown functions of BRCA1 are likely to be mediated independent of its ability to catalyze ubiquitination. The genome copy number patterns were studied on the mice tumors that lacks E3 ubiqitin ligase activity of BRCA1 and were compared to copy number profile of mice lacking p53 and both brca1 and p53. Array CGH was performed using Agilent mouse CGH microarray 244K kit. Genomic DNA isolated from tumor tissue and its corresponding mouse tail were labelled with two different dyes and hybridized simultaneously on to microarray slides to perform comparitive genomic hybridization.

ORGANISM(S): Mus musculus

SUBMITTER: Jude Kendall

PROVIDER: E-GEOD-31673 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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BRCT phosphoprotein recognition, but not E3 ligase activity, is essential for BRCA1 tumor suppression

Project description:It has been recognized that BRCA1, in the form of the BRCA1/BARD1 heterodimer, acting as an ubiquitin E3 ligase offered a possible mechanism to explain its pleiotrophic nature of BRCA1 activity. Our observation that mice lacking BRCA1 enzymatic activity are viable apart from male sterility was unexpected. Our results suggest that the E3 ligase activity of BRCA1 is largely dispensable for normal development and is not essential for all BRCA1 functions. Thus, many of the known and unknown functions of BRCA1 are likely to be mediated independent of its ability to catalyze ubiquitination. The genome copy number patterns were studied on the mice tumors that lacks E3 ubiqitin ligase activity of BRCA1 and were compared to copy number profile of mice lacking p53 and both brca1 and p53.

2011-08-26 | GSE31673 | GEO

High-resolution comparative genomic hybridization of inflammatory breast cancer and identification of candidate genes

Project description:Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC) clinical samples. Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent “complex” patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. Pre-treatment tumor tissues were collected from 197 patients with invasive adenocarcinomas. Patients underwent surgical biopsies or initial surgery at the Institut Paoli-Calmettes (IPC, Marseille, France) between 1987 and 2007. Each patient gave written informed consent and the study was approved by the IPC “Comité d’Orientation Stratégique”. Tumor samples were macrodissected and frozen in liquid nitrogen within 30 minutes of removal. Before RNA extraction, tumor sections were reviewed by two pathologists and contained more than 60% of tumor cells. Gene expression data of the 197 BCs were quantified using whole-genome DNA microarrays (HG-U133 Plus 2.0, Affymetrix).

2011-03-01 | E-GEOD-23720 | biostudies-arrayexpress

macroH2A is a BRCA1 ubiquitin ligase substrate

Project description:BRCA1/BARD1 is a macroH2A1-specific E3 ligase and implicates a role for macroH2A1 K123 ubiquitination in cellular senescence

2016-11-04 | MSV000080319 | MassIVE

BRCA1 Regulates Carbohydrate Metabolism Through its RING Domain and Transcription Factor Oct1

Project description:The tumor suppressor BRCA1 regulates DNA damage responses and multiple other processes. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal RING domain. Here we show that BRCA1 promotes oxidative metabolism via degradation of Oct1, a transcription factor with pro-glycolytic/tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells towards a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNAseq confirms the deregulation of metabolic genes. BRCA1 mediates direct Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenografts. Oct1 protein levels correlate positively with tumor aggressiveness, and inversely with BRCA1, in primary breast cancer samples. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism.

2017-11-30 | GSE98831 | GEO

Oligoarray comparative genomic hybridisation-mediated mapping of suppressors of an essential receptor tyrosine kinase generated in a deletion-biased mutagenesis screen

Project description:We have used oligoarray comparative genomic hybridization (aCGH) to identify novel suppressors generated in a UV-TMP based suppressor screen. This approach is suitable for detecting single gene mutations as well as copy number variations. Keywords: C.elegans Suppressor screen array CGH [1] 2 test samples from homozygous rol-3 suppressor strains mapped to chromosome II individually hybridized to reference DNA from BC6637 (rol-3(s1040ts) conditional strain), using a high density tiling array for chromosome II. [2] 4 test samples from homozygous rol-3 suppressor strains individually hybridized to reference DNA from BC6637 (rol-3(s1040ts) conditional strain).

2012-07-12 | E-GEOD-15224 | biostudies-arrayexpress

Agilent 244K aCGH data for colon cancer samples

Project description:Mutation of the gene PARK2 is the most common cause of early-onset Parkinson's Disease (PD)1,2. PARK2 encodes a gene product with E3 ubiquitin ligase activity3. In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2-q27 in cancer. Here, we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes, at the same residues as the germline mutations causing familial PD. Cancer-specific mutations abrogate the growth suppressive effects of PARK2. PARK2 mutations in cancer decrease the gene product's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2-q27. PARK2, a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells. Human colorectal samples were profiled on Agilent 244K aCGH arrays per manufacturer's instructions. Pooled reference normal DNA was used as the reference.

2010-06-22 | E-GEOD-18638 | biostudies-arrayexpress

Copy number profiling via ArrayCGH on high grade serous epithelial ovarian cancer samples from multiple biopsies

Project description:We performed Array CGH on 25 patients with high grade serous epithelial ovarian cancer (HGS-EOC): each of this had multiple biopsies taken at the moment of the surgery in different anatomical sites, and 18 had also temporal biopsies taken after several cycles of chemotherapy. Blood was used as control. The experiment was performed to identify genomic alterations that can be used to classify the disease, going beyond the individual tumor heterogeneity.

2019-12-19 | E-MTAB-6900 | biostudies-arrayexpress

Comparative genomic hybridization by array of human brain metastases and primary breast carcinomas

Project description:This study comprises arrayCGH data from the University clinic Eppendorf (UKE) in Hamburg. The array platform being used is the VUMC v30 30k Oligo chip

2012-03-08 | E-MTAB-354 | biostudies-arrayexpress

Genome wide analysis of copy number variation in NAFLD spectrum

Project description:Despite some success in identifying CNVs responsible for metabolic phenotypes including obesity and diabetes mellitus, there are as yet no data available to suggest whether or not CNVs might be involved in the etiology of the NAFLD spectrum. This report is a comprehensive analysis of copy number in Malaysian patients with NAFLD. Genomic DNA was extracted from blood obtained from patients with NAFLD and submitted for genome-wide analysis using aCGH

2015-02-26 | E-GEOD-55645 | biostudies-arrayexpress

CGH array profiles of melanoma cell lines

Project description:Dysfunction in type I interferon (IFN) signaling occurs in patients with stage II or more advanced cancer. After screening the effects of a panel of 12 melanoma cell lines on PBMCs of healthy volunteers of IFNalpha signal pathway, two groups of melanoma cell lines could be identified one with stronger suppression (low pSTAT-1 group) than the other (high pSTAT-1 group). Comparative genomic hybridization (CGH) identified consistent amplification of 12q22-24 as a genomic marker for the immune suppressive melanoma cell lines. This region corresponded to higher transcription of the NOS1 gene located in that region in the low pSTAT1 group and NOS1 expression was identified as causal factor in melanoma induced immune suppression. Twelve melanoma cell lines were analyzed. Genomic DNA of the cell line sample was labeled with Cy5 and reference normal PBMC DNA was labeled with Cy3.

2015-03-01 | E-GEOD-44850 | biostudies-arrayexpress

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