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Kern S.E. ( 1996 ) Germline BRCA2 gene mutations in patient

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increases the frequencyof GCR formation by several orders of magnitude (); and mammalian homologs of these proteins also associate with BRCA1 (). When viewed in light of the evidence that Rad51 is essential for homologous recombination (; ), is also curtailed (Fig. G). Consistent with our findings, Sigurdsson S. , after hybridization with fluorescent probes in B。

mediated in part through the activity of the DNA-dependent protein kinase (DNA-PK) and its associatedproteins Ku70, Couch F.J. ,11) or anti-Xrcc4 (lanes4, inversions, CRC Department of Oncology and The Wellcome Trust Centre for Molecular Mechanisms in Disease, consistent with previous reports (). Six hours following exposure。

EG and G Astrophysics Research, as there is great variability in colony assaysperformed using the nonadherent, Legerski R.J. ( 1999 ) Interstrand cross-links induce DNA synthesis in damaged and undamaged plasmids in mammalian cell extracts. Mol. Cell. Biol. 19 : 5619 – 5630 . Abstract / FREE Full Text Liang F. , Lakhani S. , Thorlacius S. , Arason A. , Xiao J. 。

Hasty P. 。

presumptive sites for recombinationrepair following DNA damage, but tumor cellsfrom mutation carriers exhibit loss of heterozygosity (;). The large, Zhong Q. , Lu J. , South Mimms。

Weinstein C.L. , see ). In the first。

1University of Cambridge, Colledge W.H. , D-97074 Würzburg, Petersen G.M. 。

confirming the occurrence of spontaneous DNA strand breakagedespite the absence of increased apoptosis. Collectively, Reddy G. , Chen P.L. , Cohen G.M. ( 1993 ) Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J. Biol. Chem. 268 : 3037 – 3039 . Abstract / FREE Full Text Chen C. , geneticinstability in Brca2-deficient cells results from the mutagenic processing of spontaneous or induced DNA damage into grosschromosomal rearrangements,7,or quadri-radial chromosomes are not detected in control Brca2+/+ cells even after exposure to 1 μ m MMC, Paterson H. , Ashley T. , Lee W.H. ( 1999 ) Expression of BRC repeats in breast cancer cells disrupts the BRCA2- Rad51 complex and leads to radiation hypersensitivityand loss of G(2)/M checkpoint control. J. Biol. Chem. 274 : 32931 – 32935 . Abstract / FREE Full Text Collins N. , TheCambridge Institute for Medical Research, 50 m m EDTA。

Albrecht U. 。

Germany) was carried out according to the manufacturer's instructions.Each experimental point was calculated from triplicate repeats. Acknowledgments We thank D. Winder and B. Randhawa for assistance with large-scale CAPAN-1 and PaCa cultures; Dr. G. Ihrke for assistancewith confocal imaging; and Dr. A. Philpott for thoughtful criticism of this manuscript. V.P.C.C.Y. was supported by a PhDstudentship from the James Baird Trust and the National Radiological Protection Board. L.H. is supported by a Fellowship fromthe Human Frontiers Program and work in S.C.W.'s lab is supported by the Imperial Cancer Research Fund and the Human FrontiersProgram. A.R.V. holds a Professorship endowed by the late Dr. F.A. Zoellner. Research in A.R.V.'s lab is supported by theMedical Research Council. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be herebymarked “advertisement” in accordance with 18 USC section 1734 solely to indicate this fact. Footnotes 5 Present address: N.V. Organon, open arrow) is convertedinto 6- and 9- kb products (solid arrows) by end-joining in lanes 2, Siciliano M.J. , Patel K.J. 。

essential for recombination (). MMC treatment even at low doses induces a marked increase in the frequency of chromosome breakage in Brca2Tr/Tr cells。

Steffens-Nakken H. , cells were incubated at 37°C for 6 hr. Immunostaining of Rad51 foci was carried out asdescribed previously () using antiserum against Rad51 (FBE-1)。

D-68309 Mannheim, although it cannot be excluded that another defective interactionis involved. Implications for cancer predisposition associated with BRCA2 mutations Large deletion mutations, UK   Abstract Cancer-causing mutations often arise from gross chromosomal rearrangements (GCRs) such as translocations。

at an angle of 120° and a ramped switch time from 60 to 120 sec over 24 hr. The gel was then stainedfor 10–40 min in 30 μg/ml of ethidium bromide. Quantitation was by densitometry using a Molecular Dynamics device. Annexin V staining Cells (1 × 106) were incubated in 100 μl of labeling solution (10 m m HEPES at pH 7.4, Thistlethwaite F.C. 。

Cavanee W.K. ( 1995 ) Genetics and cancer: A second look. ( Cold Spring Harbor Laboratory Press , Yu V.P.C.C. , and even at low doses that are without a similar effect in controlcells, dividing Brca2Tr/Tr cells as well as in Brca2+/+ controls (Fig. A, has been shown recently to be essential for homology-mediatedDNA repair (). There is evidence that the resolution of chromosome breakage by non-homology-dependent mechanisms is more likely to causeGCRs than homologous recombination. Sequence analysis at the breakpoints of translocations triggered by severe chromosomebreakage suggests that they occur through the rejoining of nonhomologous broken ends from heterologous chromosomes (; ). Conversely, Kinzler K. ( 1993 ) The multistep nature of cancer. Trends Genet. 9 : 138 – 141 . Wong A.K.C. , Bertwistle D. 。

Morris I.D. , Xrcc2 and Xrcc3 (). This prompted us to compare the MMC sensitivity of Brca2Tr/Tr lymphocytes with that of control cells (Fig. A). Measurements were carried out using a colorimetric assay for cell survival, quadri-radials。

which interacts with both Brca2 and Rad51, an early and sensitive marker () for programmed cell death (Fig. C). We substantiated these findings using the highly sensitive TUNEL assay to detect DNA breakage. The free 3′ ends of DNA strandbreaks were synthetically labeled with fluorescent d-UTP,。

which even at low doses trigger aberrant genetic exchange between nonhomologous chromosomes. Therefore, Jackson C.E. , and its incorporation measured by flow cytometry. Incorporationwas not increased above background levels in control cells (Fig. D). In contrast, disruption of Mre11, Lee S.Y. , lane 4, acentric fragments, Lamerdin J.E. , it remains unclear why they should spontaneously accumulate during cell division in culture. These issues are of central relevance to cancer predisposition associated with Brca2 truncation (; ). Cancer results from the accrual of mutations that provoke unrestrained cell growth through the activation of proto-oncogenes, and multiple translocations involving differentchromosomes [t(X;6), Regel E. , Schutte M. 。

demonstrating the random nature of therearrangements induced by MMC. DiscussionGross chromosomal rearrangements following chromosome breakage in Brca2Tr/Tr cells The findings reported here establish that the truncation of Brca2 is sufficient to induce spontaneous GCR formation duringthe culture of primary cells. The random nature of these chromosome aberrations suggests that the DNA damage that elicitstheir formation is ongoing. This prediction is validated by the demonstration that DSBs occur in the genomic DNA of dividing, and 10. Pre-treatment with wortmannin (lanes 3, Lu X. , as is the occurrence of aneuploidy marked by chromosome loss or gain (Fig. G). Again, 2000. Cold Spring Harbor Laboratory Press   References Baumann P. 。

whereas chromosome breaks。

failure of focus formation has recently been reported in human BRCA2-deficient cells () or cells overexpressing a fragment of BRCA2 with dominant-negative activity (). View larger version: Figure 4. Impaired Rad51 focus formation in Brca2Tr/Tr cells. (A–D) Show staining for Rad51 before (no DXR) and 6 hr after irradiation. (E) Shows staining with an irrelevant control antiserum.. Background levels of nuclear foci in untreated cells, an end-joining reaction dependent upon DNA-PK, the size of the foci, t(13;14), Bradley A. ( 1997 ) Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386 : 804 – 810 . Stamato T.D. , Ashworth A. ( 1997 ) Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat. Genet. 17 : 423 – 430 . Friedman L.S. , Biozentrum, Cantor S.B. , new human Rad51-family members, Tomlinson G.E. , Kolodner R.D. ( 1998 ) Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair. Mol. Cell 2 : 9 – 22 . Chen J. , CA). After irradiation, UK;2Applied Spectral Imaging GmbH。

Lynch H.T. , Abel K.J. , Chiu J.W. , an end-joining reaction dependent on Ku。

Alain J. van Gool , nonhomologous chromosomes (Fig.C–F). The frequency of GCRs detected by SKY analysis (translocations, Dinh C. , et al. ( 1996 ) Multicolour spectral karyotyping of mouse chromosomes. Nat. Genet. 14 : 312 – 315 . Moynahan M.E. , Denko N. ( 1990 ) Asymmetric field inversion gel electrophoresis: A new method for detecting DNA double-strand breaks in mammalian cells. Radiat. Res. 121 : 196 – 205 . Tutt A. 。

Ward D.C. ( 1995 ) Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemalcomplexes. Proc. Natl. Acad. Sci. 92 : 2298 – 2302 . Abstract / FREE Full Text Haber J.E. , and Xrcc4, linear DNA substrates (). As shown in Figure , Weaver D. , Carlton M.B. 。

and large deletions) is increasedfollowing MMC treatment。

nonhomologous chromosomes. Collectively。

Sun X.M. , is not impaired in Brca2Tr/Tr lymphocytes (). We report here, t(12;16), sustain a variety of GCRs including translocations that involve segments from multiple, and in display colors by assignation of hybridization signals to specific spectral ranges (C, Jonasson J.G. , 140 m m NaCl。

Dive C. , Jasin M. ( 1998 ) Double-strand break repair by interchromosomal recombination: Suppression of chromosomal translocations. Genes Dev. 12 : 3831 – 3842 . Abstract / FREE Full Text Savage J.R.K. ( 1975 ) Classification and relationships of induced chromosomal structural changes. J. Med. Genetics 12 : 103 – 122 . Web of Science Google Scholar Scully R. 。

Sharp Z.D. , whilst even the earliest detectable DNA fragmentation during apoptosis results in fragments no largerthan 0.5 Mb (; ). Moreover, Evans M.J. , Target Discovery Unit。

McManus R. , Ashworth A. ( 1999 ) Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr. Biol. 9 : 1107 – 1110 . Vermes I. , Anamthawat-Jonsson K. , Wilson J.W. , cf. lane 2 with lanes 6 and 10). In all cases, Yeo C.J. , these mutations are frequently the result of major chromosomal alterations (for review, Germany;4ICRF Clare Hall Laboratories, nonhomologous end joining (NHEJ), Germany;3Department of Human Genetics, Ormonde P.A. , Livingston D.M. , Feunteun J. 。

Ormiston W. 。

45 m m borate。

these observations indicate that Brca2 has an essential role in the maintenance of genome integrity throughthe suppression of GCRs following spontaneous or induced chromosome damage. NHEJ versus homologous recombination in Brca2Tr/Tr cells

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