Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present report deals with the functional relationships among protein complexes which, when mutated, are responsible for four human syndromes displaying cancer proneness, and whose cells are deficient in DNA double-strand break (DSB) repair. In some of them, the cells are also unable to activate the proper checkpoint, while in the others an unduly override of the checkpoint-induced arrest occurs. As a consequence, all these patients display genome instability. In ataxia-telangiectasia, the mutated protein (ATM) is a kinase, which acts as a transducer of DNA damage signalling. The defective protein in the ataxia-telangiectasia-like disorder is a DNase (the Mre11 nuclease) that in vivo produces single-strand tails at both sides of DSBs. Mre11 is always present with the Rad50 ATPase in a protein machine: the nuclease complex. In mammals, this complex also contains nibrin, the protein mutated in the Nijmegen syndrome. Nibrin confers new abilities to the nuclease complex, and can also bind to BRCA1 (one of the two proteins mutated in familial breast cancer). BRCA1 has a central motif that binds with high affinity to cruciform DNA, a structure present in places where the DNA loops are anchored to the chromosomal axis or scaffold. The BRCA1 x cruciform DNA complex should be released to allow the nuclease complex to work in DNA recombinational repair of DSBs. BRCA1 also acts as a scaffold for the assembly of ATPases such as Rad51, responsible for the somatic homologous recombination. Loss of the BRCA1 gene prevents cell survival after exposure to cross-linkers. The BRCA1-RING domain is an E3-ubiquitin ligase. It can mono-ubiquitinate the FANCD2 protein, mutated in one of the Fanconi anemia complementation groups, to regulate it. Finally, during DNA replication, the nuclease complex and its activating ATM kinase are integrated in the BRCA1-associated surveillance complex (BASC) that contains, among others, enzymes required for mismatch excision repair. In short, the proteins missing in these syndromes have in common their BRCA1-mediated assembly into multimeric machines responsible for the surveillance of DNA replication, DSB recombinational repair, and the removal of DNA cross-links.
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PMID:Human syndromes with genomic instability and multiprotein machines that repair DNA double-strand breaks. 1250 2

BRCA2 is a tumor suppressor directly implicated in familial breast cancer. Extensive genetic and biochemical characterization has shown that BRCA2 is involved in the maintenance of chromosomal stability and that it has an important role in recombination-mediated double-strand DNA break repair. Two recent structures of BRCA2 domains have revealed that it may serve as a critical mediator of DNA repair through direct interactions with Rad51, the eukaryotic homolog of RecA, and with single-stranded DNA. Before the structures were determined, little was known about the structural basis of BRCA2 interactions with the Rad51 pathway of DNA repair. Taken together, the structures provide striking insights into the role of BRCA2 in double-strand DNA break repair and suggest a direct role for BRCA2 in homologous recombination that was not evident from earlier studies.
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PMID:Structural insights into BRCA2 function. 1272 14

Immortalized cells maintain telomere length through either a telomerase-dependent process or a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Homologous recombination is implicated in the ALT pathway in both yeast and human ALT cells. In ALT cells, two types of DNA double-strand break repair and homologous recombination factors, the Rad50/Mre11/NBS1 complex and Rad51/Rad52 along with replication factors (RPA) and telomere binding proteins (TRF1 and TRF2), are associated with the ALT-associated PML body (APB). DNA synthesis in late S-G(2) is associated with APBs, which contain telomeric DNA and, are therefore, potential sites for telomere length maintenance. Here, we show that the breast cancer susceptibility gene product, breast cancer susceptibility gene 1, and the human homologue of yeast Rap1, hRap1, are also associated with APBs specifically during late S-G(2) phase of the cell cycle. We additionally show that the localization of the double-strand break repair factors with APBs is distinct from their association with ionizing radiation-induced nuclear foci. To systematically explore the mechanism involved in the assembly of APBs, we examine the role of Nijmegen breakage syndrome 1 (NBS1) and TRF1 in this process, respectively. We demonstrated that NBS1 plays a key role in the assembly and/or recruitment of Rad50, Mre11, and breast cancer susceptibility gene 1, but not Rad51 or TRF1, to APBs. The NH(2) terminus of NBS1, specifically the BRCA1 COOH-terminal domain, is required for this activity. Although TRF1 interacts with NBS1 directly, it is dispensable for the association of either Rad50/Mre11/NBS1 or Rad51 with APBs. Perturbation of the interactions between NBS1/Mre11 and APBs correlates with reduced BrdUrd incorporation associated with APBs, consistent with decreased DNA synthesis at these sites. Taken together, these results support a model in which NBS1 has a vital role in the assembly of APBs, which function to maintain telomeres in human ALT cells.
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PMID:Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1. 1275 Feb 84

Rad52 encodes a protein which is required for recombinational repair of double-strand breaks. It is also associated with breast cancer predisposition genes BRCA1 and BRCA2. Mutations in the genes Rad51 or Rad52 result in severe defects in genetic recombination and the repair of double-strand DNA breaks. In order to examine if Rad52 mutations might be involved in sporadic ovarian cancer, we analyzed two stop mutations (Ser346ter and Tyr415ter) in 142 Austrian ovarian carcinoma patients and 128 healthy volunteers. In addition, we analyzed these two mutations in 105 breast/ovarian cancer families (160 members) to examine if the mutations in Rad52 are associated with the occurrence of cancer and with mutations in the BRCA1 and BRCA2 genes. Our results show that these two mutations are rare in all three groups examined. There are no statistically significant differences in the frequencies of the Rad52 mutations between the control group and sporadic ovarian cancer patients and between the control groups and familial breast/ovarian cancer patients, indicating that these two mutations of the Rad52 do not play a major role in the initiation of sporadic ovarian carcinoma and familial breast/ovarian cancer.
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PMID:Rad52 gene mutations in breast/ovarian cancer families and sporadic ovarian carcinoma patients. 1288 40

DNA damage such as double-strand breaks presents severe difficulties for the cell to repair, especially if genetic stability is to be preserved. Recombination of the damaged DNA molecule with an undamaged homologous sequence provides a potential mechanism for the high-fidelity repair of such damage, and genes encoding homologous recombination (HR) proteins have been identified in mammalian cells. Xrcc2 is a protein with homology to Rad51, the core component of HR, but with a nonredundant role in damage repair. Here, we make the first study of the consequences of knocking out one or both copies of the Xrcc2 gene in mouse cells. In addition to growth arrest and sensitivity to agents causing severe DNA damage, we show that order-of-magnitude higher levels of chromosomal alterations are sustained in primary or immortal Xrcc2(-/-) embryonic fibroblasts. Using spectral karyotyping, we find that aneuploidy and complex chromosome exchanges, including an unexpectedly high frequency of homologue exchanges, are hallmarks of Xrcc2 deficiency. In addition, we find evidence for mild haploinsufficiency of Xrcc2. These responses are linked to several indicators of reduced HR in Xrcc2(-/-) cells, including a 30-fold reduction in gene conversion and reduced levels of Rad51-focus formation and of sister-chromatid exchange. Our data have similarities to recent studies of the disruption of breast cancer-predisposing (Brca) genes in mouse cells and are contrasted to analyses of cells carrying disruptions of genes in the other main pathway for double-strand break repair, nonhomologous end joining.
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PMID:Homologous recombination deficiency leads to profound genetic instability in cells derived from Xrcc2-knockout mice. 1467 73

The pathway determining malignant cellular transformation, which depends upon mutation of the BRCA1 tumor suppressor gene, is poorly defined. A growing body of evidence suggests that promotion of DNA double-strand break repair by homologous recombination (HR) may be the means by which BRCA1 maintains genomic stability, while a role of BRCA1 in error-prone nonhomologous recombination (NHR) processes has just begun to be elucidated. The BRCA1 protein becomes phosphorylated in response to DNA damage, but the effects of phosphorylation on recombinational repair are unknown. In this study, we tested the hypothesis that the BRCA1-mediated regulation of recombination requires the Chk2- and ATM-dependent phosphorylation sites. We studied Rad51-dependent HR and random chromosomal integration of linearized plasmid DNA, a subtype of NHR, which we demonstrate to be dependent on the Mre11-Rad50-Nbs1 complex. Prevention of Chk2-mediated phosphorylation via mutation of the serine 988 residue of BRCA1 disrupted both the BRCA1-dependent promotion of HR and the suppression of NHR. Similar results were obtained when endogenous Chk2 kinase activity was inhibited by expression of a dominant-negative Chk2 mutant. Surprisingly, the opposing regulation of HR and NHR did not require the ATM phosphorylation sites on serines 1423 and 1524. Together, these data suggest a functional link between recombination control and breast cancer predisposition in carriers of Chk2 and BRCA1 germ line mutations. We propose a dual regulatory role for BRCA1 in maintaining genome integrity, whereby BRCA1 phosphorylation status controls the selectivity of repair events dictated by HR and error-prone NHR.
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PMID:Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. 1470 43

DNA interstrand cross-links (ICL)-inducing agents such as cisplatin, mitomycin C (MMC) and nitrogen mustards are widely used as potent antitumor drugs. Although ICL repair mechanism is not yet well characterized in mammalian cells, this pathway is thought to involve a sequential action of nucleotide excision repair (NER) and homologous recombination (HR). The importance of unraveling ICL repair pathways is highlighted by the hypersensitivity to ICL-inducing agents in cells of patients with the genetic disease Fanconi anemia (FA) and in cells mutated in the Breast Cancer susceptibility genes BRCA1 and BRCA2. To better characterize the involvement of HR in the sensitivity to ICL-inducing agents, we examined spontaneous and ICL-induced HR in rodent FA-like V-H4 cells. In this report, we show that MMC-hypersensitive V-H4 cells exhibit an increased spontaneous homology-directed repair (HDR) activity compared to the resistant V79 parental cells. Elevated HDR activity results mainly in increased conservative Rad51-dependent recombination, without affecting non-conservative single-strand annealing process (SSA). We also show that HDR activity is enhanced following MMC treatment in parental cells, but not in rodent FA-like V-H4 cells. Moreover, our data indicate that Rad51 foci formation is significantly delayed in these FA-like cells in response to crosslinking agent. These findings provide evidence for an impairment of HR control in V-H4 cells and emphasize the involvement of the FA pathway in HR-mediated repair.
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PMID:Impairment of homologous recombination control in a Fanconi anemia-like Chinese hamster cell mutant. 1538 Jun 21

The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2.FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination.
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PMID:Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. 1567 Oct 39

Mutations in human BRCA2 confer an increased risk of female breast cancer. In this study, we found a novel insertion/deletion polymorphism (10204insAAA causing amino acid change M3332IK) in canine BRCA2, which is located in the putative second nuclear localization signal (NLS2) and C-terminal Rad51-binding region. The nuclear localization of the insAAA C-terminus was more efficient than localization of the delAAA sequence when NLS1 was mutated. Strong, comparable Rad51 binding was observed for both the insAAA and delAAA C-termini. Dogs with the insertion/deletion polymorphism will provide a new model for studying the function of BRCA2.
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PMID:Insertion/deletion polymorphism in the BRCA2 nuclear localization signal. 1601 3

The BACH1 helicase was initially identified by its direct binding to BRCA1 and, thus, was linked to hereditary breast cancer. More recently, BACH1 was identified as the gene defective in the J complementation group of Fanconi anemia (FA). FA is a multigenetic disorder characterized by cellular sensitivity to crosslinkers and chromosome instability. Because FANCD2 monoubiquitination is intact in BACH1 deficient cells, BACH1 appears to act downstream in the FA pathway akin to BRCA2/FANCD1. Interestingly, while BRCA1 has various interactions with FA proteins it has not been identified as an FA gene. As the race to uncover the last few unknown FA complementation groups comes to an end, future work will be required to uncover how these gene products function to combat the effects of DNA damage and maintain genomic stability. In particular, it remains elusive whether BRCA1 is functionally linked to the FA pathway through its interaction with BACH1/FANCJ. This review focuses on a model for the connection of BRCA1 to BACH1 in the FA pathway. We predict that BRCA1 regulates the BACH1 helicase activity to coordinate the timely displacement of Rad51 from nucleofilaments, promoting error free repair and ultimately maintaining chromosomal integrity.
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PMID:Assessing the link between BACH1 and BRCA1 in the FA pathway. 1635 29


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