Des mutations dans les genes FANC sont responsables de l’anemie de Fanconi (AF), une maladie genetique de phenotype complexe incluant une pancytopenie, des malformations congenitales et une predisposition elevee au cancer. L’augmentation par les agents pontant l’ADN de la frequence des aberrations chromosomiques, une caracteristique de l’AF, est utilisee pour le diagnostic. Parmi les onze genes FANC, neuf sont identifies. Huit de ces genes sont localises sur des autosomes, tandis que FANCB est situe sur le chromosome X. L'un des genes FANC est BRCA2, implique dans la predisposition genetique au cancer du sein et/ou de l’ovaire. Sept des proteines FANC s’associent pour former un complexe a geometrie variable dependant de sa localisation subcellulaire, tandis que FANCD1 (BRCA2), FANCD2, FANCI et FANCJ ne sont pas associees au complexe. La mono-ubiquitinylation de FANCD2, dependante du complexe, jouerait un role important dans la gestion des pontages de l’ADN. Les proteines FANC et BRCA1, etroitement associees, participent, entre autres, avec les proteines ATM, NBS1 et ATR, a un reseau multiproteique implique dans la detection, la signalisation et la reparation des lesions bloquant la replication de l’ADN.

In the yeast Saccharomyces cerevisiae, allelism between the psol-1 and the rev3-1 mutants on the one hand and the pso2-1 and snm1 mutants on the other, is demonstrated by the comparison of phenotypes, complementation tests and meiotic segregation analysis.

Purpose : To define the role of the ataxia telangiectasia (A-T) mutated gene (ATM) in activation and progress of apoptosis. Material and methods : Three normal and three A-T EBV-transformed cell lines were studied. Following irradiation (IR), Fas activation or ceramide exposure, viability and apoptosis were measured by trypan blue dye exclusion assay and as sub-G1 cell fraction by flow cytometric analysis of propidium iodide stained cultures, respectively. Activation of caspase-3 was evaluated by immunoblot and by an in vitro activity assay on cytosolic cell extracts. To assess changes in mitochondrial potential and reactive oxygen species, cells were stained by 3,3'-dihexyloxacarbocynine iodide or hydroethidine, respectively, and scored by flow cytometry. Results : The observations establish that A-T cells are equipped with a proficient apoptotic machinery, as demonstrated by their ability to undergo mitochondrial collapse and caspase-3 activation after Fas activation or ceramide treatment. Both treatments have a similar cytotoxic effect on normal and A-T cells. In contrast, in spite of the stronger cytotoxicity induced by IR exposure, irradiated A-T cells are unable to undergo mitochondrial collapse and caspase-3 activation. Conclusions : The data indicate that ATM is necessary in the initiation of molecular pathway(s) leading to IR-induced apoptosis, and suggest that increased radiosensitivity of A-T cells is more likely a direct consequence of necrotic cell death.

In order to better understand the relative contribution of the different UV components of sunlight to solar mutagenesis, the distribution of the bipyrimidine photolesions, cyclobutane pyrimidine dimers (CPD), (6-4) photoproducts ((6–4)PP), and their Dewar valence photoisomers (DewarPP) was examined in Chinese hamster ovary cells irradiated with UVC, UVB, or UVA radiation or simulated sunlight. The absolute amount of each type of photoproduct was measured by using a calibrated and sensitive immuno-dot-blot assay. As already established for UVC and UVB, we report the production of CPD by UVA radiation, at a yield in accordance with the DNA absorption spectrum. At biologically relevant doses, DewarPP were more efficiently produced by simulated solar light than by UVB (ratios of DewarPP to (6-4)PP of 1:3 and 1:8, respectively), but were detected neither after UVA nor after UVC radiation. The comparative rates of formation for CPD, (6-4)PP and DewarPP are 1:0.25 for UVC, 1:0.12:0.014 for UVB, and 1:0.18:0.06 for simulated sunlight. The repair rates of these photoproducts were also studied in nucleotide excision repair-proficient cells irradiated with UVB, UVA radiation, or simulated sunlight. Interestingly, DewarPP were eliminated slowly, inefficiently, and at the same rate as CPD. In contrast, removal of (6-4) photoproducts was rapid and completed 24 h after exposure. Altogether, our results indicate that, in addition to CPD and (6-4)PP, DewarPP may play a role in solar cytotoxicity and mutagenesis.

Upon UVA irradiation psoralens covalently bind to DNA as monoadduct and interstrand crosslink. Psoralen photoadducts are processed via an excision repair reaction that has been reproduced in vitro with transcriptionnally active cell-free extracts. A derived in vitro assay that allows direct quantification of the incised sites has been set up and used to compare the efficiency of the incision reaction on monoadducts and interstrand cross-links. The incision reaction was performed with HeLa cell-free extracts on angelicin or 8-methoxypsoralen (8-MOP)-modified plasmid DNA substrates carrying known amounts of mono- and biadducts, within various relative ratios. In the case of 8-MOP modified plasmids consisting in a mixture of mono- and biadducts on the same DNA molecule, the incision signal was mainly due to the presence of interstrand cross-links. The extent of incision was linear with the number of cross-links up to about 4 cross-links per plasmid and then reached a plateau. The sensitivity of incision defined as the increase of incision by 2-fold over the background level corresponded to about 1 cross-link per plasmid molecule, and about 7% of the total cross-links were repaired under our assay conditions. The incision activity on angelicin monoadducts yielded only 27% when compared to that on 8-MOP cross-links. Furthermore, 8-MOP cross-links lowered the incision extent of angelicin monoadducts when the two photoadducts were present on distinct plasmid DNA molecules. These data are in line with the more rapid excision of psoralen interstrand cross-links vs monoadducts observed in vivo.

Biology of the CellVolume 88, Issue 1-2 p. 82-82 FANCONI ANEMIA: A HUMAN SYNDROME WITH DEREGULATED APOPTOTIC PATHWAYS Agnès RIDET, Agnès RIDET UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorChristel GUILLOUF, Christel GUILLOUF UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorEric DUCHAUD, Eric DUCHAUD UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorEthel MOUSTACCHI, Ethel MOUSTACCHI UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorFilippo ROSSELLI, Filippo ROSSELLI UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this author Agnès RIDET, Agnès RIDET UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorChristel GUILLOUF, Christel GUILLOUF UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorEric DUCHAUD, Eric DUCHAUD UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorEthel MOUSTACCHI, Ethel MOUSTACCHI UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this authorFilippo ROSSELLI, Filippo ROSSELLI UMR 218 du CNRS, LRC n°1 du CEA, 26 rue d'Ulm, Institut Curie, Recherche, 75231 Paris cedex 05, FranceSearch for more papers by this author First published: 1996 https://doi.org/10.1016/S0248-4900(97)86894-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume88, Issue1-21996Pages 82-82 RelatedInformation

Biology of the CellVolume 84, Issue 1-2 p. 95-95 Photosensitization by psoralens: Mitochondria structural modifications in fanconi anemia fibroblasts as compared to normal human fibroblasts Solange Rousset, Solange Rousset CNRS URA 1292, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.Search for more papers by this authorSilvano Nocentini, Silvano Nocentini CNRS URA 1292, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.Search for more papers by this authorEthel Moustacchi, Ethel Moustacchi CNRS URA 1292, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.Search for more papers by this author Solange Rousset, Solange Rousset CNRS URA 1292, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.Search for more papers by this authorSilvano Nocentini, Silvano Nocentini CNRS URA 1292, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.Search for more papers by this authorEthel Moustacchi, Ethel Moustacchi CNRS URA 1292, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.Search for more papers by this author First published: 1995 https://doi.org/10.1016/0248-4900(96)81366-9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume84, Issue1-21995Pages 95-95 RelatedInformation

In this paper, we have compared mutant frequency data at the hprt locus in circulating T-lymphocytes from four large datasets obtained in the UK (Sussex), the USA (Vermont), France (Paris) and The Netherlands (Leiden). In total, data from > 500 non-exposed individuals ranging in age from newborns (cord blood samples) to > 80 years old have been included in the analysis. Based on raw data provided by the four laboratories, a model is presented for the analysis of mutant frequency estimations for population monitoring. For three of the laboratories, a considerable body of data was provided on replicate estimates of mutant frequency from single blood samples, as well as estimates from repeat blood samples obtained over a period of time from many of the individual subjects. This enabled us to analyse the sources of variation in the estimation of mutant frequency. Although some variation was apparent in the results from the four laboratories, overall the data were in general agreement. Thus, in all laboratories, cellular cloning efficiency of T-cells was generally high (> 30%), although in each laboratory considerable variation between experiments and subjects was seen. Mutant frequency per clonable T-cell was in general found to be inversely related to cloning efficiency. With the exception of a few outliers (which are to be expected), mutant frequencies at this locus were in the same range in each dataset; no effect of subject gender was found, but an overall clear age effect was apparent. When log mutant frequency was analysed vs log (age + 0.5) a consistent trend from birth to old age was seen. In contrast, the effect of the smoking habit did differ between the laboratories, there being an association of smoking with a significant increase in mutant frequency in the Sussex and Leiden datasets, but not in those from the Vermont or Paris datasets. Possible reasons for this are discussed. One of the objectives of population monitoring is an ability to detect the effect of accidental or environmental exposure to mutagens and carcinogens among exposed persons. The large body of data from non-exposed subjects we have analysed in this paper has enabled us to estimate the size of an effect that could be detected, and the number of individuals required to detect a significant effect, taking known sources of variation into account. We now suggest that, given the variation between subjects that is seen, large sample sizes (30–50 subjects per subject category) may be required to have a 90% chance of detecting increases 1.5-fold above the control level, while rather smaller samples (∼ 20 per group) would be required to detect a 2-fold increase.

Biology of the CellVolume 79, Issue 1 p. 84-84 IMMUNOELECTRON MICROSCOPY ON DNA: A TOOL FOR PHOTOBIOLOGY ROUSSET Solange, ROUSSET Solange Institut Curie, Biologie, URA 1292 CNRS, 26 ore d'UIm, 75231 Paris Cedex 05Search for more papers by this authorNOCENTINI Silvano, NOCENTINI Silvano Institut Curie, Biologie, URA 1292 CNRS, 26 ore d'UIm, 75231 Paris Cedex 05Search for more papers by this authorMOUSTACCHI Ethel, MOUSTACCHI Ethel Institut Curie, Biologie, URA 1292 CNRS, 26 ore d'UIm, 75231 Paris Cedex 05Search for more papers by this author ROUSSET Solange, ROUSSET Solange Institut Curie, Biologie, URA 1292 CNRS, 26 ore d'UIm, 75231 Paris Cedex 05Search for more papers by this authorNOCENTINI Silvano, NOCENTINI Silvano Institut Curie, Biologie, URA 1292 CNRS, 26 ore d'UIm, 75231 Paris Cedex 05Search for more papers by this authorMOUSTACCHI Ethel, MOUSTACCHI Ethel Institut Curie, Biologie, URA 1292 CNRS, 26 ore d'UIm, 75231 Paris Cedex 05Search for more papers by this author First published: 1993 https://doi.org/10.1016/0248-4900(93)90276-KCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume79, Issue11993Pages 84-84 RelatedInformation