EMSY Links the BRCA2 Pathway to Sporadic Breast and Ovarian Cancer

Hughes-Davies, Luke; Huntsman, David G.; Ruas, Margarida; Fuks, François; Bye, Jacqueline M.; Chin, Suet-Feung; Milner, J.; Brown, Lindsay; Hsu, Forrest D.; Gilks, Blake; Nielsen, Torsten O.; Schulzer, Michael; Chia, Stephen; Ragaz, Joseph; Cahn, Anthony; Linger, Lori; Özdağ, Hilal; Cattaneo, Elena; Jordanova, Ekaterina S.; Schuuring, Edward; Yu, David S.; Venkitaraman, Ashok R.; Ponder, Bruce A.J.; Doherty, Aidan J.; Aparicio, Samuel; Bentley, David; Theillet, Charles; Ponting, Chris P.; Caldas, Carlos; Kouzarides, Tony

doi:10.1016/s0092-8674(03)00930-9

Cited by 381 publications

(423 citation statements)

References 33 publications

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“…Highlighting a role of histone modification in the regulation of flavonoid gene expression, we show that H3K9/14 acetylation is intimately associated with the recruitment of R to DNA. We identified R-interacting factor 1 (RIF1) as a nuclear maize factor with homology to the BRCA2-interacting EMSY N-terminal region (the ENT domain), which specifically interacts with the bHLH region of R. EMSY associates with ''Royal Family'' domain proteins (HP1 and BS69), and it relocalizes to sites of DNA damage, consistent with the role of chromatin remodeling in DNA repair (17). RIF1 is an example of how plants combined the ENT domain and a royal family domain (i.e., AGENET) into one protein.…”

mentioning

confidence: 80%

The basic helix–loop–helix domain of maize R links transcriptional regulation and histone modifications by recruitment of an EMSY-related factor

Hernandez

Feller

Morohashi³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The control of anthocyanin accumulation in maize by the cooperation of the basic helix-loop-helix (bHLH) protein R with the MYB transcription factor C1 provides one of the best examples of plant combinatorial transcriptional control. Establishing the function of the bHLH domain of R has remained elusive, and so far no proteins that interact with this conserved domain have been identified. We show here that the bHLH domain of R is dispensable for the activation of transiently expressed genes yet is essential for the activation of the endogenous genes in their normal chromatin environment. The activation of A1, one of the anthocyanin biosynthetic genes, is associated with increased acetylation of histone 3 (H3) at K9/K14 in the promoter region to which the C1/R complex binds. We identified R-interacting factor 1 (RIF1) as a nuclear, AGENET domain-containing EMSY-like protein that specifically interacts with the bHLH region of R. Knockdown experiments show that RIF1 is necessary for the activation of the endogenous promoters but not of transiently expressed genes. ChIP experiments established that RIF1 is tethered to the regulatory region of the A1 promoter by the C1/R complex. Together, these findings describe a function for the bHLH domain of R in linking transcriptional regulation with chromatin functions by the recruitment of an EMSY-related factor.anthocyanin ͉ BRCA2 ͉ chromatin T he evolution of multicellular organisms was accompanied by an increase in the complexity of gene regulatory mechanisms, reflected in the dramatic expansion of transcription factor families and in the intricate interactions between regulatory proteins and cis-regulatory elements in what is commonly known as combinatorial transcriptional control. Superimposed on this complexity is the understanding that histone modifications and chromatin structure are intimately linked to the regulatory activity of many transcription factors (1). Establishing the interactions between combinatorial gene regulation and histone functions thus poses a problem of significant biological importance.The basic helix-loop-helix (bHLH) family of transcription factors is among the largest in animals and plants (2). bHLH domains are characterized by the presence of an Ϸ18-residue hydrophilic basic helix followed by two amphipathic ␣-helices separated by a loop (3, 4). When present, basic regions contribute to the binding of bHLH factors to DNA, through cisregulatory elements, termed E-boxes, with the CANNTG consensus, whereas HLH motifs participate in homodimer or heterodimer formation (4). Maize R was the first plant bHLH transcription factor described (5). R belongs to a small gene family, which includes B, and R/B specify anthocyanin pigmentation in different plant tissues (6). They participate in the transcriptional regulation of the anthocyanin pathway genes through the cooperation with the R2R3-MYB transcription factor C1 or its paralog, PL1 (7). C1 and R/B physically interact through the MYB domain of C1 and the N-terminal region of R (which does not contai...

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confidence: 80%

The basic helix–loop–helix domain of maize R links transcriptional regulation and histone modifications by recruitment of an EMSY-related factor

Hernandez

Feller

Morohashi³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…47 CCND1 and EMSY amplifications have both been associated with poor overall survival, 47,48 but there is no a straightforward association between CCND1 amplification and expression, and CCND1 expression has been associated with ER and good survival. 49 The mechanism for the frequent co-amplification of genes spread over different chromosomes is yet unclear.…”

Section: Co-amplified Regionsmentioning

confidence: 99%

Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes

et al. 2010

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Several oncogenes and tumor-suppressor genes have been shown to be implicated in the development, progression and response to therapy of invasive breast cancer. The phenotypic uniqueness (and thus the heterogeneity of clinical behavior) among patients' tumors may be traceable to the underlying variation in gene copy number of these genes. To obtain a more complete view of gene copy number changes and their relation to phenotype, we analyzed 20 breast cancer-related genes in 104 invasive breast cancers with the use of multiplex ligation-dependent probe amplification (MLPA). We identified MYC gene amplification in 48% of patients, PRDM14 in 34%, topoisomerase IIa (TOP2A) in 32%, ADAM9 in 32%, HER2 in 28%, cyclin D1 (CCND1) in 26%, EMSY in 25%, IKBKB in 21%, AURKA in 17%, FGFR1 in 17%, estrogen receptor alpha (ESR1) in 16%, CCNE1 in 12% and EGFR in 9% of patients. There was a significant correlation between the number of amplified genes and the histological grade and mitotic index of the tumor. Gene amplifications of EGFR, CCNE1 and HER2 were negatively associated with estrogen receptor status whereas FGFR1, ADAM9, IKBKB and TOP2A revealed a positive association. Amplifications of ESR1, PRDM14, MYC and HER2 were associated with a high mitotic index, and PRDM14 and HER2 amplifications with high histological grade. MYC amplification was detected more frequently in ductal tumors and high-level MYC amplifications were significantly associated with large tumor size. HER2/MYC, HER2/CCNE1 and EGFR/MYC co-amplified tumors were significantly larger than tumors with either of these amplifications. Gene loss occurred most frequently in E-cadherin (CDH1) (20%) and FGFR1 (10%). In conclusion, MLPA analysis with this 'breast cancer kit' allowed to simultaneously assess copy numbers of 20 important breast cancer genes, providing an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and thereby data on the potential importance of these genes in breast cancer.

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“…This review has not touched upon the contributions of BRCA1 and BRCA2 to checkpoint functions [150][151][152], transcriptional regulation [153,154], gene silencing [81,82,155], telomere function [96] or (for BARD1) mRNA processing [156,157]. Both HR and non-HR functions of BRCA genes might account for the tissue specificity of cancer risk in BRCA gene mutation carriers [158] and the latter may be important modulators of the clinical phenotypes associated with BRCA gene inactivation.…”

Section: When the Levee Breaks: Dsgs Genomic Instability And Cancermentioning

confidence: 99%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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EMSY Links the BRCA2 Pathway to Sporadic Breast and Ovarian Cancer

Cited by 381 publications

References 33 publications

The basic helix–loop–helix domain of maize R links transcriptional regulation and histone modifications by recruitment of an EMSY-related factor

The basic helix–loop–helix domain of maize R links transcriptional regulation and histone modifications by recruitment of an EMSY-related factor

Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

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