Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation
Genes & DevelopmentPublished 1 June 2000Open access
Veronica Yu, Michael Köehler, Claus Steinlein, Michael Schmid, Leslyn A. Hanakahi, Alain J. van Gool
Citations323
SJR quartileQ1
SJR score4.00
SNIP1.43
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TL;DR
It is shown that murine Brca2 has an essential function in suppressing GCR formation after chromosome breakage, providing a mechanistic basis for cancer predisposition.
Abstract
Cancer-causing mutations often arise from gross chromosomal rearrangements (GCRs) such as translocations, which involve genetic exchange between nonhomologous chromosomes. Here we show that murine Brca2 has an essential function in suppressing GCR formation after chromosome breakage. Cells that harbor truncated Brca2 spontaneously incur GCRs and genomic DNA breaks during division. They exhibit hypersensitivity to DNA damage by interstrand cross-linkers, which even at low doses trigger aberrant genetic exchange between nonhomologous chromosomes. Therefore, genetic instability in Brca2-deficient cells results from the mutagenic processing of spontaneous or induced DNA damage into gross chromosomal rearrangements, providing a mechanistic basis for cancer predisposition.
Keywords
Biochemistry, Genetics and Molecular Biology
Journal of Immunological MethodsA novel assay for apoptosis Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V
5,319 Citations1995I. Vermes, C. Haanen +2 more
The Annexin V assay offers the possibility of detecting early phases of apoptosis before the loss of cell membrane integrity and permits measurements of the kinetics of apoptotic death in relation to the cell cycle.
Trends in GeneticsThe multistep nature of cancer
1,852 Citations1993Bert Vogelstein, Kenneth W. Kinzler
Three to six mutations appear to be required to complete the process of cellular multiplication associated with gradual increases in tumor size, disorganization and malignancy in cancer.
CellAssociation of BRCA1 with Rad51 in Mitotic and Meiotic Cells
1,463 Citations1997Ralph Scully, Junjie Chen +6 more
Findings suggest a functional interaction between BRCA1 and Rad51 in the meiotic and mitotic cell cycles, which, in turn, suggests a role for BRC a1 in the control of recombination and of genome integrity.
Molecular CellBrca1 Controls Homology-Directed DNA Repair
1,228 Citations1999Mary Ellen Moynahan, Joanne W Chiu +2 more
A caretaker role for BRCA1 is demonstrated in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes.
The EMBO JournalApoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation.
1,139 Citations1993F Oberhammer, James W. Wilson +6 more
Results suggest that changes in the integrity of DNA indicative of the release of chromatin loop domains occur before cleavage at internucleosomal sites is initiated and that the latter is not an essential step in the apoptotic process.
NatureEmbryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2
1,070 Citations1997Shyam K. Sharan, Masami Morimatsu +8 more
Developmental arrest in Brca2-deficient embryos, their radiation sensitivity, and the association of Brca1 with Rad51 indicate that Brca 2 may be an essential cofactor in the Rad51-dependent DNA repair of double-strand breaks, thereby explaining the tumour-suppressor function of BrCA2.
CellHuman Rad51 Protein Promotes ATP-Dependent Homologous Pairing and Strand Transfer Reactions In Vitro
683 Citations1996Peter Baumann, Fiona E. Benson +1 more
The results establish hRad51 as a functional homolog of RecA, but indicate that the human protein and its bacterial counterpart differ in their ability to promote extensive strand transfer.
PubMedGermline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.
647 Citations1996Michael Goggins, Mieke Schutte +9 more
The results suggest that some familial risks for carcinoma will be evident only through a population-based application of gene screening techniques because a low disease penetrance of the germline mutations in some families often evades clinical suspicion.
Proceedings of the National Academy of SciencesHomology-directed repair is a major double-strand break repair pathway in mammalian cells
642 Citations1998Feng‐Xia Liang, Mingguang Han +2 more
Analysis of the spectrum of repair events at a defined chromosomal break by using direct physical analysis of repair products demonstrates the importance of homologous recombination in the repair of DSBs in mammalian cells.
ScienceAssociation of BRCA1 with the hRad50-hMre11-p95 Complex and the DNA Damage Response
632 Citations1999Qing Zhong, Chi‐Fen Chen +7 more
It is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin that is important for the cellular responses to DNA damage that are mediated by the h Rad50-hMre 11-p95 complex.
Molecular CellInvolvement of Brca2 in DNA Repair
631 Citations1998Ketan J. Patel, Veronica Yu +8 more
Findings define a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome and Fanconi anemia.
Molecular CellStable Interaction between the Products of the BRCA1 and BRCA2 Tumor Suppressor Genes in Mitotic and Meiotic Cells
629 Citations1998Junjie Chen, Daniel P. Silver +9 more
BRCA1 and BRCA2 participate, together, in a pathway(s) associated with the activation of double-strand break repair and/or homologous recombination and Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/ or ovarian cancer.
Proceedings of the National Academy of SciencesNuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes.
552 Citations1995Thomas Haaf, Efim I. Golub +3 more
It is concluded that the mammalian proteins homologous to yeast Rad51 are involved in repair of DNA damage and recombinational repair during meiosis.
Journal of Biological ChemistryRAD51 Interacts with the Evolutionarily Conserved BRC Motifs in the Human Breast Cancer Susceptibility Gene brca2
535 Citations1997Alexander Wong, Ralph Pero +3 more
The detailed mapping of additional domains that are involved in interactions between the human homologs of these two proteins are reported, suggesting that the BRC repeats function to bind RAD51.
Molecular CellXRCC2 and XRCC3, New Human Rad51-Family Members, Promote Chromosome Stability and Protect against DNA Cross-Links and Other Damages
533 Citations1998Nan Liu, Jane E. Lamerdin +15 more
Characterization of these genes and sequence alignments reveal that XRCC2 andXRCC3 are members of an emerging family of Rad51-related proteins that likely participate in homologous recombination to maintain chromosome stability and repair DNA damage.
Journal of Medical GeneticsClassification and relationships of induced chromosomal structual changes.
456 Citations1976John R. K. Savage
A detailed survey is given of the types and classification of primary structural changes that can be induced in chromosomes and observed at the first metaphase after the initial damage.
Genes & DevelopmentDouble-strand break repair by interchromosomal recombination: suppression of chromosomal translocations
447 Citations1998Christine Richardson, Mary Ellen Moynahan +1 more
It is found that recombination is induced at least 1000-fold following the introduction of a DSB in one repeat, and the lack of crossover events that would have led to translocations supports a model in which recombinations is coupled to replication.
Nature GeneticsTumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation
432 Citations1997Frances Connor, David Bertwistle +6 more
It is shown that Brca2 is required for efficient DNA repair, and the results suggest that loss of the p53 checkpoint may be essential for tumour progression triggered by mutations in BRCA2.
Journal of Biological ChemistryDexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation.
415 Citations1993David G. Brown, Xiaoming Sun +1 more
The formation of these high molecular weight fragments, despite the inhibition by zinc of the endonuclease cleavage of DNA, suggests that key enzyme(s), other than the Ca2+/Mg(2+)-dependent end onuclease, are involved at the earliest stages of induction of apoptosis.
PubMedBRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo.
414 Citations1999Shyng‐Shiou F. Yuan, Sou Ying Lee +4 more
A requirement of BRCA2 protein for the IR-induced assembly of Rad51 complex in vivo is suggested, suggesting a need for homologous recombination and recombinational repair of DNA double-strand breaks in familial breast cancers.
Nature GeneticsGross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants
407 Citations1999Clark Chen, Richard D. Kolodner
A novel mutator assay in S. cerevisiae is developed that allows specific detection of GCR formation and suggests that at least three distinct pathways can suppress GCRs: two that suppress microhomology-mediated G CRs (RFA1 and RAD27) and one that suppresses non-homology–mediated GCRS (RAD50/MRE11/XRS2).
Proceedings of the National Academy of SciencesThe BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment
390 Citations1998Phang‐Lang Chen, Chi‐Fen Chen +4 more
The results suggest that the interaction between the BRC repeats of BRCA2 and RAD51 is critical for cellular response to DNA damage caused by MMS.
NatureSynergistic actions of Rad51 and Rad52 in recombination and DNA repair
376 Citations1998Fiona E. Benson, Peter Baumann +1 more
Yeast Rad51 has been shown to interact with Rad52 protein, as does the human homologue, and it is shown that hRad52 stimulates homologous pairing by hRad51, indicating that Rad52 is involved in an early stage of Rad51-mediated recombination.
Current BiologyAbsence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification
316 Citations1999Andrew Tutt, Anastasia Gabriel +6 more
It is reported that Brca2(Tr2014/Tr2014) MEFs frequently develop micronuclei, suggesting a potential mechanism whereby loss of BRCA2 may, within subclones, drive the loss of cell-cycle regulation genes, enabling proliferation and tumourigenesis.
Nature GeneticsMulticolour spectral karyotyping of mouse chromosomes
309 Citations1996Marek Liyanage, Allen Coleman +11 more
Spectral karyotyping (SKY) is applied to chemically induced plasmocytomas, mammary gland tumours from transgenic mice overexpressing the c-myc onco-gene and thymomas from mice deficient for the ataxia telangiectasia (Atm) gene to demonstrate the potential of SKY to identify complex chromosomal aberrations in mouse models of human carcinogenesis.
Proceedings of the National Academy of SciencesDNA end-joining catalyzed by human cell-free extracts
293 Citations1998Peter Baumann, Stephen C. West
Using cell-free extracts prepared from human lymphoblastoid cell lines, an in vitro system for end-joining has been developed andIntermolecular ligation was found to be accurate and to depend on DNA ligase IV/Xrcc4 and requires Ku70, Ku86, and DNA-PKcs, the three subunits of the DNA-activated protein kinase DNA- PK.
PubMedConsistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13.
243 Citations1995Nadine Collins, Ross McManus +8 more
The data suggest that both alleles of BRCA2 are inactivated in cancers, the pattern expected of a recessive oncogene or tumour suppressor gene.
Mutation Research/DNA Repair ReportsIsolation and cross-sensitivity of X-ray-sensitive mutants of V79-4 hamster cells
206 Citations1987Nigel J. Jones, Roger Cox +1 more
The V79-4 Chinese hamster line was mutagenized and surviving clones screened for X-ray sensitivity using a replica microwell technique, and 3 clearly sensitive clones were isolated from approximately 5000 screened, and designated irs 1 to irs 4.
Journal of Biological ChemistryExpression of BRC Repeats in Breast Cancer Cells Disrupts the BRCA2-Rad51 Complex and Leads to Radiation Hypersensitivity and Loss of G2/M Checkpoint Control
199 Citations1999Chi‐Fen Chen, Phang‐Lang Chen +3 more
The results strongly suggest that the interaction between BRCA2 and Rad51 mediated by BRC repeats is critical for the cellular response to DNA damage.
PubMedDifferent tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13.
159 Citations1995Jūlı́us Guðmundsson, Guðrún Jóhannesdóttir +5 more
The results suggest that BRCA2 is a tumor suppressor gene and may be involved in the tumorigenesis of several cancer types in addition to breast cancer.
Molecular CellChromosomal Rearrangements Occur in S. cerevisiae rfa1 Mutator Mutants Due to Mutagenic Lesions Processed by Double-Strand-Break Repair
156 Citations1998Clark C. Chen, Keiko Umezu +1 more
Three temperature-sensitive S. cerevisiae RFA1 alleles were found to cause elevated mutation rates, which resulted from the accumulation of base substitutions, frameshifts, gross deletions, and nonreciprocal translocations, similar to the breakpoint structures observed at translocations and gross deleting events, including LOH events, underlying human cancer and other hereditary diseases.
Radiation ResearchAsymmetric Field Inversion Gel Electrophoresis: A New Method for Detecting DNA Double-Strand Breaks in Mammalian Cells
151 Citations1990Thomas D. Stamato, Nicholas Denko
Overall, the above results indicate that AFIGE is a sensitive method for detecting DSBs in DNA.
Proceedings of the National Academy of SciencesLack of chromosome territoriality in yeast: Promiscuous rejoining of broken chromosome ends
137 Citations1996James E. Haber, Wai-Ying Leung
The broken ends of mitotic chromosomes are free to search the entire genome for appropriate partners and are not functionally confined to isolated domains of the nucleus, at least when chromosomes are broken.
PubMedBRCA2 and p53 mutations in primary breast cancer in relation to genetic instability.
133 Citations1998Sólveig Grétarsdóttir, Steinunn Thorlacius +7 more
Tumors with mutations in either BRCA2 or p53 gene had multiple chromosomal abnormalities, as shown by cytogenetic analysis.
PubMedThymic lymphomas in mice with a truncating mutation in Brca2.
132 Citations1998Lori S. Friedman, Fiona Thistlethwaite +10 more
A mutation in the mouse Brca2 gene that terminates translation in exon 11 at 45% of the normal transcript length is created, which suggests a correlation with genotype analogous to that previously reported in humans.
Molecular and Cellular BiologyIllegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome.
116 Citations1994John W. Phillips, W.F. Morgan
Molecular and Cellular BiologyInterstrand Cross-Links Induce DNA Synthesis in Damaged and Undamaged Plasmids in Mammalian Cell Extracts
66 Citations1999Lei Li, Carolyn A. Peterson +3 more
This system provides a biochemical assay for investigating mechanisms of interstrand cross-link repair and should also facilitate the identification and functional characterization of cellular proteins involved in repair of these lesions.
Molecular and Cellular BiologyIllegitimate Recombination Induced by DNA Double-Strand Breaks in a Mammalian Chromosome
49 Citations1994John W. Phillips, William F. Morgan
DNA double-strand-break-induced mutations in the endogenous adenine phosphoribosyl-transferase (APRT) gene in cultured Chinese hamster ovary cells after exposure to restriction endonucleases indicate that blunt-end DNA double- STRands can induce illegitimate (nonhomologous) recombination in mammalian chromosomes and that they play an important role in mutagenesis.
Current BiologyDNA repair: Rad52 – the means to an end
33 Citations1999Kevin Hiom
In eukaryotic organisms, double-strand breaks in chromosomal DNA are repaired either by non-homologous end-joining, or by homologous recombination, and cells choose which pathway to use.
Cold Spring Harbor Laboratory Press eBooksGenetics and cancer : a second look
14 Citations1995Bruce A.J. Ponder, Webster K. Cavenee +1 more
Prospects for cancer genetics, R.A. Weinberg the genetic epidemiology of cancer, E.E. Claus metabolic polymorphisms and cancer susceptibility, G.S. Smith, et al genetics of embryonal tumours of childhood - retinoblastoma, Wilms' tumour and neuroblastoma.