Showing papers by "Alan Ashworth published in 2004"
TL;DR: There are properties that define 'BRCAness' — that is, traits that some sporadic cancers share with those occurring in either BRCA1- or BRCa2-mutation carriers, which might have important implications for the clinical management of these cancers.
Abstract: Germline mutations in the BRCA1, BRCA2 and Fanconi anaemia genes confer cancer susceptibility, and the proteins encoded by these genes have distinct functions in related DNA-repair processes. Emerging evidence indicates that these processes are disrupted by numerous mechanisms in sporadic cancers. Collectively, there are properties that define 'BRCAness' — that is, traits that some sporadic cancers share with those occurring in either BRCA1- or BRCA2-mutation carriers. These common properties might have important implications for the clinical management of these cancers.
1,554 citations
TL;DR: The genes that undergo this phenomenon are described and possible mechanisms that allow haploinsufficiency to display a phenotype and facilitate the pathogenesis of cancer are discussed.
236 citations
TL;DR: Findings suggest that FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion.
Abstract: Fanconi anaemia (FA) is a chromosomal instability disorder characterized by cellular sensitivity to DNA interstrand crosslinking agents and a high risk of cancer. Six of the eight proteins encoded by the known FA genes form a nuclear complex which is required for the monoubiquitination of the FANCD2 protein. FANCD2 complexes and colocalizes with BRCA1, but its presumptive role in DNA repair has not yet been clearly defined. We used yeast two-hybrid analysis to test for interaction between FANCD2 and 10 proteins involved in homologous recombination repair. FANCD2 did not interact with RAD51, the five RAD51 paralogs, RAD52, RAD54 or DMC1. However, it bound to a highly conserved C-terminal site in BRCA2 that also binds FANCG/XRCC9. FANCD2 and BRCA2 can be coimmunoprecipitated from cell extracts of both human and Chinese hamster wild-type cells, thus confirming that the interaction occurs in vivo. Formation of nuclear foci of FANCD2 was normal in the BRCA2 mutant CAPAN-1 cells, which indicates that the recruitment of FANCD2 to sites of DNA-repair is independent of wild-type BRCA2 function. FANCD2 colocalized with RAD51 in foci following treatment with mitomycin C or hydroxyurea, and colocalized very tightly with PCNA after treatment with hydroxyurea. These findings suggest that FANCD2 may have a role in the cellular response to stalled replication forks or in the repair of replication-associated double-strand breaks, irrespective of the type of primary DNA lesion.
228 citations
TL;DR: It is shown that like BRCA2, DSS1 is required for DNA damage‐induced RAD51 focus formation and for the maintenance of genomic stability, indicating a function conserved from lower eukaryotes to humans.
Abstract: BRCA2 is a breast cancer susceptibility gene implicated in the repair of double-strand breaks by homologous recombination with RAD51. BRCA2 associates with a 70-amino-acid protein, DSS1, but the functional significance of this interaction has remained unclear. Recently, deficiency of a DSS1 orthologue in the fungus Ustilago maydis has been shown to cause a defect in recombinational DNA repair. Here we have investigated the consequences of DSS1 depletion in mammalian cells. We show that like BRCA2, DSS1 is required for DNA damage-induced RAD51 focus formation and for the maintenance of genomic stability, indicating a function conserved from lower eukaryotes to humans. However, DSS1 seems to be not required for BRCA2 or RAD51 stability or for BRCA2 and RAD51 to interact, raising the possibility that DSS1 may be required for the BRCA2–RAD51 complex to become associated with sites of DNA damage.
118 citations
TL;DR: The recent development of gene expression microarray and related technologies provides an opportunity to perform more detailed profiling of the disease and it is anticipated that the molecular classification arising from such studies will be more powerful than its pathological predecessor at confining treatment to those patients who are most likely to benefit.
Abstract: Breast cancers are routinely subcategorised on the basis of clinical stage, cellular morphology and immunohistochemical analysis of a small number of markers. The recent development of gene expression microarray and related technologies provides an opportunity to perform more detailed profiling of the disease. It is anticipated that the molecular classification arising from such studies will be more powerful than its pathological predecessor at confining treatment to those patients who are most likely to benefit. It is likely that this will result in a much less frequent use of adjuvant chemotherapy. Furthermore, of those who do receive it, a higher proportion will benefit. If adopted, this will offer considerable patient benefits in terms of reducing unnecessary toxicity and have major health economic implications.
100 citations
TL;DR: LKB1, the product of a tumour suppressor gene, is a serine/threonine kinase that coordinates disparate cellular processes, providing new insight into the regulation of cell polarity and energy-generating metabolism.
65 citations
Patent•
30 Nov 2004TL;DR: In this paper, it was shown that inhibition of the base excision repair pathway is selectively lethal in cells which are deficient in HR dependent DNA DSB repair, such as PARP.
Abstract: The present invention relates to the recognition that inhibition of the base excision repair pathway is selectively lethal in cells which are deficient in HR dependent DNA DSB repair. Methods and means relating to the treatment of cancers which are deficient in HR dependent DNA DSB repair using inhibitors which target base excision repair components, such as PARP, is provided herein.
60 citations
TL;DR: Investigating BRCA2 in distantly related organisms is likely to help to elucidate how the dysfunction of this gene leads to tumourigenesis.
14 citations
TL;DR: It is shown that Fanconi anemia complementation group B is caused by mutations in a previously uncharacterized gene located on the X chromosome, which identifies FANCB as a potential weak link in a key DNA-repair and tumor-suppressor pathway.
Abstract: A new study shows that Fanconi anemia complementation group B is caused by mutations in a previously uncharacterized gene located on the X chromosome. Its unique chromosomal localization identifies FANCB as a potential weak link in a key DNA-repair and tumor-suppressor pathway.
7 citations
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TL;DR: A panoply of functions have been proposed for the BRCA1 cancer susceptibility protein, particularly in the response to DNA damage and in transcriptional regulation, but this complexity is now exacerbated by the discovery of a distinct splice variant of BrcA1, BRCa1/IRIS, with a previously uncharacterized function in DNA replication.
Abstract: A panoply of functions have been proposed for the BRCA1 cancer susceptibility protein, particularly in the response to DNA damage and in transcriptional regulation. This complexity is now exacerbated by the discovery of a distinct splice variant of BRCA1, BRCA1/IRIS, with a previously uncharacterized function in DNA replication. This has implications for understanding tumorigenesis in BRCA1 mutation carriers.
7 citations
Patent•
30 Nov 2004
TL;DR: The authors concerne la reconnaissance du fait que l'inhibition de la voie de reparation d'excision de base est selectivement letale dans des cellules qui sont deficientes en reparation DSB dependant de la HR.
Abstract: L'invention concerne la reconnaissance du fait que l'inhibition de la voie de reparation d'excision de base est selectivement letale dans des cellules qui sont deficientes en reparation d'ADN DSB dependant de la HR. L'invention concerne des procedes et des moyens se rapportant au traitement de cancers qui sont deficients en reparation d'ADN DSB dependant de la HR a l'aide d'inhibiteurs qui ciblent des composants de reparation d'excision de base, par exemple PARP.
Patent•
12 Mar 2004
TL;DR: In this paper, the authors define a set of composes de formule (CDF) for a noyau aromatique eventuellement substitue and fusionne, in which each composes of A and B represent an ensemble of ingredients, including C5-20 aryle, C3-20 heterocyclyle, amido, thioamido, ester, acyle, and sulfonyle.
Abstract: L'invention concerne des composes de formule (I): dans laquelle A et B representent ensemble un noyau aromatique eventuellement substitue et fusionne; X peut designer NRX ou CRXRY; si X = NRX alors n prend la valeur de 1 ou 2 et si X = CRXRY alors n prend la valeur de 1; RX est selectionne dans le groupe comprenant H, C1-20 alkyle eventuellement substitue, C5-20 aryle, C3-20 heterocyclyle, amido, thioamido, ester, acyle, et des groupes sulfonyle; RY est selectionne parmi H, hydroxy, amino; ou RX et RY peuvent former ensemble spiro-C3-7 cycloalkyle ou un groupe heterocyclyle; RC1 et RC2 representent tous deux l'hydrogene ou quand X designe CRX RY, RC1, RC2, RX et RY, conjointement avec les atomes de carbone auxquels ils sont fixes, ils peuvent former un noyau aromatique eventuellement substitue et fusionne; et R1 est selectionne parmi H et halo.