Secondary literature sources for BRCT
The following references were automatically generated.
- Nelson AC, Holt JT
- Impact of RING and BRCT domain mutations on BRCA1 protein stability,localization and recruitment to DNA damage.
- Radiat Res. 2010; 174: 1-13
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Mutations within the tumor suppressor BRCA1 cause the majority ofhereditary breast and ovarian cancers. The BRCA1 protein is an importantregulator of DNA double-strand break repair, and BRCA1-deficient cells arehighly sensitive to ionizing radiation. Furthermore, BRCA1 function maycontribute to enforcement of the G(2) cell cycle checkpoint. E3-ubiquitinligase activity is the only known enzymatic activity of BRCA1, which ismediated by the N-terminal RING finger domain. The C-terminal BRCT repeatdomain, which mediates protein-protein interactions, is the only otheridentified structural domain. By investigating cancer-linked mutationswithin each domain, we demonstrate that truncation of the BRCT domaingreatly impairs the stability and nuclear localization of BRCA1 protein. Amissense mutation within the RING domain does not affect these biochemicalproperties. However, both mutant forms of BRCA1 fail to colocalize innuclear foci with the known BRCA1-interacting proteins BARD1 and BACH1,which are important for DNA repair. This failure occurs despite thecontinued ability of the RING mutant protein to interact with BACH1 andthe ability of the BRCT mutant to interact with BARD1. Furthermore,neither mutant form of BRCA1 is recruited into DNA damage-associated focimarked by gamma-H2AX. Therefore, our data suggest that both the RING andBRCT domains of BRCA1 are required for an early step in the function ofBRCA1 during DNA repair: recruitment to the sites of DNA damage.
- Moore HC et al.
- The RNA helicase p68 modulates expression and function of the Delta133isoform(s) of p53, and is inversely associated with Delta133p53 expressionin breast cancer.
- Oncogene. 2010; 29: 6475-84
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The RNA helicase p68 is a potent co-activator of p53-dependenttranscription in response to DNA damage. Previous independent studies haveindicated that p68 and the Delta133p53 isoforms, which modulate thefunction of full-length p53, are aberrantly expressed in breast cancers.Here we identify a striking inverse association of p68 and Delta133p53expression in primary breast cancers. Consistent with these findings,small interfering RNA depletion of p68 in cell lines results in ap53-dependant increase of Delta133p53 in response to DNA damage,suggesting that increased Delta133p53 expression could result fromdownregulation of p68 and provide a potential mechanistic explanation forour observations in breast cancer. Delta133p53alpha, which has been shownto negatively regulate the function of full-length p53, reciprocallyinhibits the ability of p68 to stimulate p53-dependent transcription fromthe p21 promoter, suggesting that Delta133p53alpha may be competing withp68 to regulate p53 function. This hypothesis is underscored by ourobservations that p68 interacts with the C-terminal domain of p53,co-immunoprecipitates 133p53alpha from cell extracts and interacts onlywith p53 molecules that are able to form tetramers. These data suggestthat p68, p53 and 133p53alpha may form part of a complex feedbackmechanism to regulate the expression of Delta133p53, with consequentmodification of p53-mediated transcription, and may modulate the functionof p53 in breast and other cancers that harbour wild-type p53.
- Wu Q et al.
- Transcriptional regulation during p21WAF1/CIP1-induced apoptosis in humanovarian cancer cells.
- J Biol Chem. 2002; 277: 36329-37
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In this study we used adenovirus vector-mediated transduction of eitherthe p53 gene (rAd-p53) or the p21(WAF1/CIP1) gene (rAd-p21) to mimic bothp53-dependent and -independent up-regulation of p21(WAF1/CIP1) within ahuman ovarian cancer cell line, 2774, and the derivative cell lines,2774qw1 and 2774qw2. We observed that rAd-p53 can induce apoptosis in both2774 and 2774qw1 cells but not in 2774qw2 cells. Surprisingly,overexpression of p21(WAF1/CIP1) also triggered apoptosis within these twocell lines. Quantitative reverse transcription-PCR analysis revealed thatthe differential expression of BAX, BCL2, and caspase 3 genes, specific inrAd-p53-induced apoptotic cells, was not altered in rAd-p21-inducedapoptotic cells, suggesting p21(WAF1/CIP1)-induced apoptosis through apathway distinguishable from p53-induced apoptosis. Expression analysis of2774qw1 cells infected with rAd-p21 on 60,000 cDNA microarrays identified159 genes in response to p21(WAF1/CIP1) expression in at least one timepoint with 2.5-fold change as a cutoff. Integration of the data with theparallel microarray experiments with rAd-p53 infection allowed us toextract 66 genes downstream of both p53 and p21(WAF1/CIP1) and 93 genes inresponse to p21(WAF1/CIP1) expression in a p53-independent pathway. Thegenes in the former set may play a dual role in both p53-dependent andp53-independent pathways, and the genes in the latter set gave amechanistic molecular explanation for p53-independentp21(WAF1/CIP1)-induced apoptosis. Furthermore, promoter sequence analysissuggested that transcription factor E2F family is partially responsiblefor the differential expression of genes following p21(WAF1/CIP1). Thisstudy has profound significance toward understanding the role ofp21(WAF1/CIP1) in p53-independent apoptosis.
- Yarden RI, Brody LC
- BRCA1 interacts with components of the histone deacetylase complex.
- Proc Natl Acad Sci U S A. 1999; 96: 4983-8
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Germ-line mutations in the BRCA1 tumor-suppressor gene are associated withan increased susceptibility to breast and ovarian cancer. BRCA1 contains acarboxyl-terminal domain (BRCT) that is shared with several other proteinsinvolved in maintaining genome integrity. In an effort to understand thefunction of BRCA1, we sought to isolate proteins that interact with theBRCT domain. Purified BRCT polypeptide was used as a probe to screen ahuman placenta cDNA expression library by Far Western analysis. Here wereport that BRCA1 interacts in vivo and in vitro with the Rb-bindingproteins, RbAp46 and RbAp48, as well as with Rb. Moreover, the BRCT domainassociates with the histone deacetylases HDAC1 and HDAC2. These resultsdemonstrate that BRCA1 interacts with components of the histonedeacetylase complex, and therefore may explain the involvement of BRCA1 inmultiple processes such as transcription, DNA repair, and recombination.
- Jackson P, Yardley G
- Distinct distal and proximal p53-binding sites in the MCK promoter governthe transcriptional response to p53.
- FEBS Lett. 1997; 406: 271-4
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We have investigated the functional importance of nucleotide sequencedifferences between proximal (P-) and distal (D-) p53-binding elements inthe MCK promoter. P- and D-elements normally co-operate to permitsynergistic promoter activation by p53. Interestingly, we find thatP-elements cannot co-operate with each other. In contrast, co-operationbetween D-binding sites results in levels of p53-induced transcription farhigher than those obtained by co-operation between P- and D-elements.These studies imply that distinct D- and P-p53-binding sites in the MCKpromoter may dictate the promoter response to p53.