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PubMed1993

Genetic identification, sequence, and alternative splicing of the Caenorhabditis elegans alpha 2(IV) collagen gene.

The nematode Caenorhabditis elegans has two type IV collagen genes homologous to the mammalian alpha 1(IV) and alpha 2(IV) collagen genes. We demonstrate by transgenic rescue of mutant animals that the genetic locus encoding the C. elegans alpha 2(IV) collagen gene is let-2 on the X chromosome. The most severe effect of mutations in let-2 is temperature-sensitive embryonic lethality. The embryonic lethal phenotype is similar to that seen in animals with mutations in the alpha 1(IV) collagen gene, emb-9. The sequence of the entire C. elegans alpha 2(IV) collagen gene is presented. Comparisons with mammalian type IV collagen sequences show high amino acid sequence conservation in the C-terminal NCl domain and of crosslinking residues (Cys and Lys) in the N-terminal 7S domain. RT-PCR analysis shows that transcripts of the C. elegans alpha 2(IV) collagen gene are alternatively spliced. Transcripts contain one of two mutually exclusive exons, exon 9 or 10. These exons encode very similar products, differing primarily in the sequence of a 9-10 amino acid Gly-X-Y interruption. The expression of these alternatively spliced alpha 2(IV) collagen transcripts is developmentally regulated. In embryos over 90% of the alpha 2(IV) collagen mRNA contains exon 9, while larval and adult RNAs contain 80-90% exon 10. This shift in expression of alternative alpha 2(IV) collagen transcripts suggests that C. elegans embryos may require a different form of alpha 2(IV) collagen than do larvae and adults.

Alternative Splicing↗

PubMed1994

Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase.

The control of cellular iron homeostasis involves the coordinate post-transcriptional regulation of ferritin mRNA translation and transferring receptor mRNA stability. These regulatory events are mediated by a soluble cytoplasmic protein, iron regulatory factor (IRF), which binds specifically to mRNA hairpin structures, termed iron-responsive elements (IREs), in the respective mRNAs. IRF is modulated by variations of cellular iron levels and exists as either an apo-protein or a [4Fe-4S]-cluster protein. The two conformations show distinct, mutually exclusive functions. High-affinity IRE binding is observed with the apo-form induced by iron deprivation, but is lost under high iron conditions when IRF is converted to the [4Fe-4S]-cluster form which shows cytoplasmic aconitase activity. Moreover, IRE binding is inactivated by the sulfhydryl-oxidizing agent diamide and fully activated in vitro by 2% 2-mercapto-ethanol, whereas alkylation of IRF inhibits IRE binding. In the present study, we analyzed each of the above features using site-directed mutants of recombinant human IRF. The results support the bifunctional nature of IRF. We conclude that cysteines 437, 503 and 506 anchor the [4Fe-4S]-cluster, and are essential to the aconitase activity. Mutagenesis changing any of the cysteines to serine leads to constitutive RNA binding in 0.02% 2-mercaptoethanol. Cysteine 437 is particularly critical to the RNA-protein interaction. The spontaneous or diamide-induced formation of disulfide bonds between cysteines 437 and 503 or 437 and 506, in apo-IRF, as well as its alkylation by N-ethylmaleimide, inhibit binding to the IRE.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitate Hydratase↗

PubMed2026

Cooccurrence of Homologous Recombination Deficiency and Mismatch Repair Deficiency in Colorectal Cancer.

Homologous recombination deficiency (HRD) in colorectal cancer (CRC) remains largely unexplored. In contrast, mismatch repair deficiency (dMMR) occurs in ∼15% of patients with CRC. Although HRD and dMMR have historically been regarded as mutually exclusive, emerging evidence suggests that this mutual exclusivity may not be absolute. Here, we conducted a retrospective cohort study utilizing genomic and transcriptomic data to define HRD status in a Chinese dMMR CRC cohort (n = 99). Multiple machine learning approaches were employed to analyze the expression profiles of these tumors and to develop a classifier distinguishing HRD from homologous recombination proficiency (HRP) in dMMR CRCs. In the Chinese dMMR CRC cohort, 66% of tumors were classified as HRD. Compared with the HRP group, the HRD group had a significantly higher tumor mutational burden and better outcomes. The derived expression signature, comprising eight genes, successfully predicted HRD status in dMMR tumors with high accuracy in the training set (AUC = 0.88, Naïve Bayes) and the test set (AUC = 0.87). In this study, a subset of dMMR CRC tumors with co-occurring HRD was identified, which may have potential implications for patient stratification and the application of targeted therapies, such as PARP inhibitors, in this molecular subgroup.

colorectal cancer↗

PubMed1997

Splice-junction elements and intronic sequences regulate alternative splicing of the Drosophila myosin heavy chain gene transcript.

The Drosophila muscle myosin heavy chain (Mhc) gene primary transcript contains five alternatively spliced exon groups (exon 3, 7, 9, 11 and 15), each of which contains two to five mutually exclusive members. Individual muscles typically select a specific alternative exon from each group for incorporation into the processed message. We report here on the cis-regulatory mechanisms that direct the processing of alternative exons in Mhc exon 11 in individual muscles using transgenic reporter constructs, RT-PCR and directed mutagenesis. The 6.0-kilobase exon 11 domain is sufficient to direct the correct processing of exon 11 alternatives, demonstrating that the alternative splicing cis-regulatory elements are local to Mhc exon 11. Mutational analysis of Mhc exon 11 reveals that the alternative exon nonconsensus 5'-splice donors are essential for alternative splicing regulation in general, but do not specify alternative exons for inclusion in individual muscles. Rather, we show, through exon substitutions and deletion analyses, that a 360-nucleotide intronic domain precisely directs the normal processing of one exon, Mhc exon 11e, in the indirect flight muscle. These and other data indicate that alternative exons are regulated in appropriate muscles through interactions between intronic alternative splice-specificity elements, nonconsensus exon 11 splice donors and, likely, novel exon-specific alternative splicing factors.

Alternative Splicing↗

PubMed2003

Regulation of the rat phenylethanolamine N-methyltransferase gene by transcription factors Sp1 and MAZ.

The rat phenylethanolamine N-methyltransferase (PNMT) gene promoter contains 1-base pair (bp) overlapping consensus sequences for Sp1 and MAZ transcription factors at -48 and -38 bp, respectively. Gel mobility assays using PC-12-derived RS1 cell nuclear extracts or in vitro translated proteins showed that Sp1 and MAZ specifically bind to these elements, that MAZ displaces/prevents Sp1 binding, and that Sp1 and MAZ binding is mutually exclusive, with occupancy dependent on each factor's concentration and affinity for its consensus element. In transfection assays, PNMT promoter activation by Sp1 and MAZ depends on promoter length, with -893 bp of sequence yielding greatest activation. Although MAZ has higher affinity for its binding element, it is a less effective activator. Changes in PNMT promoter activity for the constructs pGL3RP60 or pGL3RP893 using a fixed amount of MAZ expression construct and a variable amount of Sp1 expression construct or vice versa confirmed the latter. Mutation of the MAZ or Sp1 sites in pGL3RP60 attenuated but did not eliminate PNMT promoter activity, even though the proteins no longer bind to their consensus elements. Phosphatase treatment of RS1 cell nuclear extracts prevented MAZ- and Sp1-DNA binding complex formation. Although MAZ and Sp1 elevate endogenous PNMT mRNA in RS1 cells, MAZ preferentially increases intron-retaining whereas Sp1 preferentially increases intronless mRNA. Thus, expression of the PNMT gene seems to be modulated through competitive binding of phosphorylated Sp1 and MAZ to their consensus elements in the promoter. In addition, post-transcriptional regulation seems to be another important mechanism controlling PNMT expression.

Animals↗

PubMed1993

The NF-kappa B and Sp1 motifs of the human immunodeficiency virus type 1 long terminal repeat function as novel thyroid hormone response elements.

We report that thyroid hormone (T3) receptor (T3R) can activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). Purified chick T3R-alpha 1 (cT3R-alpha 1) binds as monomers and homodimers to a region in the LTR (nucleotides -104 to -75 [-104/-75]) which contains two tandem NF-kappa B binding sites and to a region (-80/-45) which contains three Sp1 binding sites. In contrast, human retinoic acid receptor alpha (RAR-alpha) and mouse retinoid X receptor beta (RXR-beta) do not bind to these elements. However, RXR-beta binds to these elements as heterodimers with cT3R-alpha 1 and to a lesser extent with RAR-alpha. Gel mobility shift assays also revealed that purified NF-kappa B p50/65 or p50/50 can bind to one but not both NF-kappa B sites simultaneously. Although the binding sites for p50/65, p50/50, and T3R, or Sp1 and T3R, overlap, their binding is mutually exclusive, and with the inclusion of RXR-beta, the major complex is the RXR-beta-cT3R-alpha 1 heterodimer. The NF-kappa B region of the LTR and the NF-kappa B elements from the kappa light chain enhancer both function as T3 response elements (TREs) when linked to a heterologous promoter. The TREs in the HIV-1 NF-kappa B sites appear to be organized as a direct repeat with an 8- or 10-bp gap between the half-sites. Mutations within the NF-kappa B motifs which eliminate binding of cT3R-alpha 1 also abolish stimulation by T3, indicating that cT3R-alpha 1 binding to the Sp1 region does not independently mediate activation by T3. The Sp1 region, however, is converted to a functionally strong TRE by the viral tat factor. These studies indicate that the HIV-1 LTR contains both tat-dependent and tat-independent TREs and reveal the potential for T3R to modulate other genes containing NF-kappa B- and Sp1-like elements. Furthermore, they indicate the importance of other transcription factors in determining whether certain T3R DNA binding sequences can function as an active TRE.

Base Sequence↗

PubMed2005

A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye.

A critical question about signal transduction is how weak or transient activation of signaling pathways achieves a robust and long-term switch in gene expression. We report that a microRNA is part of a mechanism that makes cells sensitive to signals in the Drosophila eye. Expression of miR-7 is activated in cells as they begin differentiating into photoreceptors. This is dependent on EGF receptor (EGFR) signaling that triggers ERK-mediated degradation of the transcription factor Yan. In nonstimulated cells, Yan represses miR-7 transcription, whereas miR-7 RNA represses Yan protein expression in photoreceptors, by binding to sequences within its mRNA 3'UTR. We propose that reciprocal negative feedback between Yan and miR-7 ensures mutually exclusive expression, with Yan in progenitor cells and miR-7 in photoreceptor cells. Expression is switched when EGFR signaling transiently triggers Yan degradation. This two-tiered mechanism explains how signal transduction activity can robustly generate a stable change in gene-expression patterns.

Animals↗

PubMed1980

Influence of amino acid starvation on guanosine 5'-diphosphate 3'-diphosphate basal-level synthesis in Escherichia coli.

We observed that the synthesis of basal-level guanosine 5'-diphosphate 3'-diphosphate (ppGpp) in both relA mutants and relA+ relC strains of Escherichia coli decreased in response to amino acid limitation and that this was accompanied by an increase in ribonucleic acid (RNA) synthesis. Addition of the required amino acid to starved cultures of relaxed bacteria resulted in the resumption of ppGpp synthesis and a concomitant decrease in RNA production. Our results indicate that relA mutants retain a stringent factor-independent ribosomal mechanism for basal-level ppGpp synthesis. They also suggest that in relA+ bacteria, stringent factor-mediated ppGpp synthesis and the production of basal-level ppGpp are mutually exclusive. These findings substantiate the hypothesis that there are two functionally discrete mechanisms for ppGpp synthesis in E. coli. Through these studies we have also obtained new evidence which indicates that ppGpp serves as a modulator of RNA synthesis during balanced growth as well as under conditions of nutritional downshift and starvation.

Amino Acids↗

PubMed2003

A bipartite mechanism for ERK2 recognition by its cognate regulators and substrates.

Mitogen-activated protein (MAP) kinases control gene expression in response to extracellular stimuli and exhibit exquisite specificity for their cognate regulators and substrates. We performed a structure-based mutational analysis of ERK2 to identify surface areas that are important for recognition of its interacting proteins. We show that binding and activation of MKP3 by ERK2 involve two distinct protein-protein interaction sites in ERK2. Thus, the common docking (CD) site composed of Glu-79, Tyr-126, Arg-133, Asp-160, Tyr-314, Asp-316, and Asp-319 are important for high affinity MKP3 binding but not essential for ERK2-induced MKP3 activation. MKP3 activation requires residues Tyr-111, Thr-116, Leu-119, Lys-149, Arg-189, Trp-190, Glu-218, Arg-223, Lys-229, and His-230 in the ERK2 substrate-binding region, located distal to the common docking site. Interestingly, many of the residues important for MKP3 recognition are also used for Elk1 binding and phosphorylation. In addition to the shared residues, there are also residues that are unique to each target recognition. There is evidence indicating that the CD site and the substrate-binding region defined here are also utilized for MEK1 recognition, and indeed, we demonstrate that the binding of MKP3, Elk1, and MEK1 to ERK2 is mutually exclusive. Taken together, our data suggest that the efficiency and fidelity of ERK2 signaling is achieved by a bipartite recognition process. In this model, one part of the ERK2-binding proteins (e.g. the kinase interaction motif sequence) docks to the CD site located on the back side of the ERK2 catalytic pocket for high affinity association, whereas the interaction of the substrate-binding region with another structural element (e.g. the FXFP motif in MKP3 and Elk1) may not only stabilize binding but also provide contacts crucial for modulating the activity and/or specificity of ERK2 target molecules.

Amino Acid Motifs↗

PubMed1991

Inheritance of phenotype in mammalian cells: genetic vs. epigenetic mechanisms.

Inherited phenotypic changes in cultured cells, as observed during differentiation and transformation, reflect alterations in gene expression and have both a genetic and epigenetic basis. The causes of specific changes are often difficult to define especially when observing phenomenological end points. Although such observations are an important step in defining the phenotypic changes that endure for multiple generations, it is necessary to analyze cells at the molecular level to characterize the pathways leading to changes in phenotype. Gene expression can be regulated at multiple levels, i.e., DNA structure, gene transcription, and/or posttranscriptional modifications. Four genetic mechanisms (DNA point mutations, deletion, rearrangement, and amplification) and two epigenetic mechanisms (DNA methylation and the preservation of DNA-protein complexes) can account for the majority of enduring changes observed in cultured cells. Genetic alterations in DNA sequence appear to be largely responsible for altered growth regulation associated with transformation, but there is also evidence to suggest that epigenetic mechanisms play a role in transformation. Differentiation of cultured cells is often associated with lack of growth, and has been ascribed in part to epigenetic mechanisms. However, differentiation and transformation are not mutually exclusive but may be regulated by parallel multistep pathways. Analysis of the causes underlying transformation has been complicated by the use of aneuploid cells, but it is clear that the tools for overcoming the ambiguities associated with phenomenological analysis are available.

Animals↗

PubMed1994

Posttranscriptional mRNA processing as a mechanism for regulation of human A1 adenosine receptor expression.

The human A1 adenosine receptor gene contains six exons with exons 1, 2, 3, 4, and part of 5 representing 5' untranslated regions. Reverse transcription-PCR with exon-specific primers showed two distinct transcripts containing either exons 3, 5, and 6 or exons 4, 5, and 6, with exons 3 and 4 being mutually exclusive. No mature mRNAs containing exons 1 and 2 have been detected. All human tissues that express any A1 receptors contain mRNA with exons 4, 5, and 6. Tissues which express high levels of A1 receptors contain mRNA with exons 3, 5, and 6. Exon 4 contains two upstream ATG codons whereas exon 3 contains none. COS cells transfected with expression vectors containing exon 4 (exons 1-6, 3-6, or Ex4-6) express much lower levels of A1 receptors than vectors without exon 4 (exons 3, 5, and 6). Mutation of upstream ATG codons in exon 4 leads to 3- to 7-fold increased A1 receptor expression, up to the level seen with the construct containing exons 3, 5, and 6. Thus, in human tissues "basal" levels of A1 receptors can be expressed by use of mRNA containing exons 4, 5, and 6, but when high levels are needed, alternative transcripts with exons 3, 5, and 6 are produced.

Alternative Splicing↗

PubMed2005

The evolutionary language game: an orthogonal approach.

Evolutionary game dynamics have been proposed as a mathematical framework for the cultural evolution of language and more specifically the evolution of vocabulary. This article discusses a model that is mutually exclusive in its underlying principals with some previously suggested models. The model describes how individuals in a population culturally acquire a vocabulary by actively participating in the acquisition process instead of passively observing and communicate through peer-to-peer interactions instead of vertical parent-offspring relations. Concretely, a notion of social/cultural learning called the naming game is first abstracted using learning theory. This abstraction defines the required cultural transmission mechanism for an evolutionary process. Second, the derived transmission system is expressed in terms of the well-known selection-mutation model defined in the context of evolutionary dynamics. In this way, the analogy between social learning and evolution at the level of meaning-word associations is made explicit. Although only horizontal and oblique transmission structures will be considered, extensions to vertical structures over different genetic generations can easily be incorporated. We provide a number of simplified experiments to clarify our reasoning.

Biological Evolution↗

PubMed2001

Nuclear factors bind to a conserved DNA element that modulates transcription of Anopheles gambiae trypsin genes.

The Anopheles gambiae trypsin family consists of seven genes that are transcribed in the gut of female mosquitoes in a temporal coordinated and mutually exclusive manner, suggesting the involvement of a complex transcription regulatory mechanism. We identified a highly conserved 12-nucleotide motif present in all A. gambiae and Anopheles stephensi trypsin promoters. We investigated the role of this putative trypsin regulatory element (PTRE) in controlling the transcription of the trypsin genes. Gel shift experiments demonstrated that nuclear proteins of A. gambiae cell lines formed two distinct complexes with probes encompassing the PTRE sequence. Mapping of the binding sites revealed that one of the complex has the specificity of a GATA transcription factor. Promoter constructs containing mutations in the PTRE sequence that selectively abolished the binding of either one or both complexes exerted opposite effects on the transcriptional activity of trypsin promoters in A. gambiae and Aedes aegypti cell lines. In addition, the expression of a novel GATA gene was highly enriched in A. gambiae guts. Taken together our data prove that factors binding to the PTRE region are key regulatory elements possibly involved in the blood meal-induced repression and activation of transcription in early and late trypsin genes.

Amino Acid Sequence↗

PubMed2005

Genetic instability induced by overexpression of DNA ligase I in budding yeast.

Recombination and microsatellite mutation in humans contribute to disorders including cancer and trinucleotide repeat (TNR) disease. TNR expansions in wild-type yeast may arise by flap ligation during lagging-strand replication. Here we show that overexpression of DNA ligase I (CDC9) increases the rates of TNR expansion, of TNR contraction, and of mitotic recombination. Surprisingly, this effect is observed with catalytically inactive forms of Cdc9p protein, but only if they possess a functional PCNA-binding site. Furthermore, in vitro analysis indicates that the interaction of PCNA with Cdc9p and Rad27p (Fen1) is mutually exclusive. Together our genetic and biochemical analysis suggests that, although DNA ligase I seals DNA nicks during replication, repair, and recombination, higher than normal levels can yield genetic instability by disrupting the normal interplay of PCNA with other proteins such as Fen1.

Acetyltransferases↗

PubMed2001

A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.

X-linked inhibitor-of-apoptosis protein (XIAP) interacts with caspase-9 and inhibits its activity, whereas Smac (also known as DIABLO) relieves this inhibition through interaction with XIAP. Here we show that XIAP associates with the active caspase-9-Apaf-1 holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspase-9, which becomes exposed after proteolytic processing of procaspase-9 at Asp315. Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition. We note that the N-terminal four residues of caspase-9 linker peptide share significant homology with the N-terminal tetra-peptide in mature Smac and in the Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding motifs. Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3. Our studies reveal a mechanism in which binding to the BIR3 domain by two conserved peptides, one from Smac and the other one from caspase-9, has opposing effects on caspase activity and apoptosis.

Amino Acid Motifs↗

PubMed1995

Mutually exclusive interactions between factors binding to adjacent Sp1 and AT-rich elements regulate gastrin gene transcription in insulinoma cells.

The gastrin gene is transiently expressed in fetal pancreatic islets during islet neogenesis but then switched off after birth when islet cells become fully differentiated. Previous studies identified a cis-regulatory sequence between -109 and -75 in the human gastrin promoter which binds islet cell-specific activators and a nonspecific repressor and thus may act as a molecular switch. The present study identified another cis-regulatory sequence (-163ACACTAAATGAAAGGGCGGGGCAG-140) which bound two islet nuclear proteins in a mutually exclusive manner, as defined by gel shift competition, methylation interference, and DNase I foot-printing assays. The general transactivator Sp1 recognized the downstream GGGCGGGG sequence, but Sp1 binding was prevented when another islet factor bound to the adjacent AT-rich sequence (CTAAATGA). This gastrin AT-rich element is nearly identical to the binding site (ATAAATGA) for the islet-specific transcription factor beta TF-1. However, the gastrin AT-binding factor appeared to differ from beta TF-1 in its gel mobility shift pattern. Transfections of rat insulinoma cells revealed that mutations which blocked binding to the AT-rich element but allowed Sp1 binding up-regulated transcriptional activity. These results suggest that the gastrin AT-binding factor blocks transactivation by Sp1 and may have a role in the repression of gastrin transcription seen at the end of islet differentiation.

Adenine↗

PubMed1997

Expression of p21WAF1/CIP1 in fetal and adult tissues: simultaneous analysis with Ki67 and p53.

AIMS: To determine the expression of p21WAF1/CIP1 in relation to the expression of Ki67 and p53 in various normal adult and fetal tissues, and to investigate its distribution throughout the cell cycle. METHODS: The expression of p21WAF1/CIP1 in relation to Ki67 and p53 was analysed in adult and fetal tissues using immunohistochemical techniques. Heat induced epitope retrieval techniques were used to characterise the presence of p21WAF1/CIP1 in different tissues, as well as to detect its distribution throughout the cell cycle. In addition, flow cytometry and western blotting were used to test whether the level of p21WAF1/CIP1 expression varied at different phases of the cell cycle in phytohaemagglutinin (PHA) stimulated lymphocytes. RESULTS: p21WAF1/CIP1 expression varied from one tissue to another, and it was restricted mainly to the squamous and glandular epithelium, where it appeared in association with p53. Human tissues in which p21WAF1/CIP1 was found showed a mutually exclusive topographical sequential expression between p21WAF1/CIP1 and Ki67. This was confirmed by double labelling studies, which showed that p21WAF1/CIP1 positive cells were in the G0 phase. Unlike these findings of a decline in p21WAF1/CIP1 expression after the G0 phase, PHA stimulated lymphocytes showed a level of p21WAF1/CIP1 expression that rose as the cell progressed through the cell cycle. CONCLUSIONS: The analysis of p21WAF1/CIP1 expression in relation to the status of p53 should take into account the existence of variable p21WAF1/CIP1 expression in different tissues. This could provide an explanation for the varying frequency of p53 mutations in tumours of different cellular origin. In tissues characterised by regular p21WAF1/CIP1 expression, it appears in a pattern that is consistent with the proposed role of this inhibitor of cyclin dependent kinases in cell cycle arrest-that of inducing cell differentiation. The conflicting results of in vivo and in vitro studies could support the hypothesis that microenvironmental conditions may influence the location of p21WAF1/CIP1 in different phases of the cell cycle.

Adult↗

PubMed2002

Highlight: BRCA1 and BRCA2 proteins in breast cancer.

Heterozygous carriers of loss-of-function germline mutations in the BRCA1 or BRCA2 breast cancer susceptibility genes have a predisposition to breast and ovarian cancer. Multiple functions have been ascribed to the products of these genes, linking them to pathways that inhibit progression to neoplasia. Various investigators have assigned roles for these tumor suppressor gene products in the cell functions of genome repair, transcription, and growth control. There is emerging evidence that BRCA1 may participate in ubiquitin E3 ligase activity. BRCA1 and BRCA2 have each been implicated in chromatin remodeling dynamics via protein partnering. Ubiquitin ligase and chromatin remodeling activities need not be mutually exclusive and both may function in DNA repair, transcriptional regulation, or cell cycle control. Here we highlight certain recent findings and currently unanswered questions regarding BRCA1 and BRCA2 in breast cancer.

BRCA1 Protein↗