Home LiteratureArticle Details
PMID: 10837032 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation.

Genes & development ·Vol. 14 ·No. 11 ·2000-06-01 ·Pages 1400-6

Yu VP, Koehler M, Steinlein C, Schmid M, Hanakahi LA, van Gool AJ, West SC, Venkitaraman AR

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.

MeSH Terms
Animals Annexin A5/metabolism BRCA2 Protein Cells, Cultured Chromosome Aberrations Chromosomes/genetics Cross-Linking Reagents/pharmacology DNA Damage DNA Repair/genetics DNA-Binding Proteins/genetics Flow Cytometry Gene Silencing Genetic Predisposition to Disease In Situ Nick-End Labeling Karyotyping Liver/embryology Mice Mitomycin/pharmacology Mutagenesis Neoplasm Proteins/genetics Rad51 Recombinase Recombination, Genetic Transcription Factors/genetics Translocation, Genetic
Chemicals
Annexin A5 BRCA2 Protein Cross-Linking Reagents DNA-Binding Proteins Neoplasm Proteins Transcription Factors Mitomycin Rad51 Recombinase Rad51 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Yu V P
University of Cambridge, CRC Department of Oncology and The Wellcome Trust Centre for Molecular Mechanisms in Disease, The Cambridge Institute for Medical Research, Cambridge CB2 2XY, UK.
Koehler M
Steinlein C
Schmid M
Hanakahi L A
van Gool A J
West S C
Venkitaraman A R
References (38)
38 references, click to expand
  1. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5287-92 PMID: 9560268
  2. Interstrand cross-links induce DNA synthesis in damaged and undamaged plasmids in mammalian cell extracts.
    Mol Cell Biol. 1999 Aug;19(8):5619-30 PMID: 10409751
  3. Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13.
    Cancer Res. 1995 Nov 1;55(21):4830-2 PMID: 7585515
  4. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2.
    Nature. 1997 Apr 24;386(6627):804-10 PMID: 9126738
  5. DNA end-joining catalyzed by human cell-free extracts.
    Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14066-70 PMID: 9826654
  6. Illegitimate recombination induced by DNA double-strand breaks in a mammalian chromosome.
    Mol Cell Biol. 1994 Sep;14(9):5794-803 PMID: 8065314
  7. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
    Mol Cell. 1998 Sep;2(3):317-28 PMID: 9774970
  8. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.
    Cancer Res. 1996 Dec 1;56(23):5360-4 PMID: 8968085
  9. Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control.
    J Biol Chem. 1999 Nov 12;274(46):32931-5 PMID: 10551859
  10. BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability.
    Cancer Res. 1998 Mar 1;58(5):859-62 PMID: 9500438
  11. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation.
    J Biol Chem. 1993 Feb 15;268(5):3037-9 PMID: 8428979
  12. Double-strand break repair by interchromosomal recombination: suppression of chromosomal translocations.
    Genes Dev. 1998 Dec 15;12(24):3831-42 PMID: 9869637
  13. Brca1 controls homology-directed DNA repair.
    Mol Cell. 1999 Oct;4(4):511-8 PMID: 10549283
  14. Homology-directed repair is a major double-strand break repair pathway in mammalian cells.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5172-7 PMID: 9560248
  15. Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes.
    Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2298-302 PMID: 7892263
  16. Thymic lymphomas in mice with a truncating mutation in Brca2.
    Cancer Res. 1998 Apr 1;58(7):1338-43 PMID: 9537225
  17. Involvement of Brca2 in DNA repair.
    Mol Cell. 1998 Feb;1(3):347-57 PMID: 9660919
  18. Asymmetric field inversion gel electrophoresis: a new method for detecting DNA double-strand breaks in mammalian cells.
    Radiat Res. 1990 Feb;121(2):196-205 PMID: 2305038
  19. Multicolour spectral karyotyping of mouse chromosomes.
    Nat Genet. 1996 Nov;14(3):312-5 PMID: 8896561
  20. Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro.
    Cell. 1996 Nov 15;87(4):757-66 PMID: 8929543
  21. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2.
    J Biol Chem. 1997 Dec 19;272(51):31941-4 PMID: 9405383
  22. Dna repair: Rad52 - the means to an end.
    Curr Biol. 1999 Jun 17;9(12):R446-8 PMID: 10375523
  23. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation.
    Nat Genet. 1997 Dec;17(4):423-30 PMID: 9398843
  24. XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages.
    Mol Cell. 1998 May;1(6):783-93 PMID: 9660962
  25. Synergistic actions of Rad51 and Rad52 in recombination and DNA repair.
    Nature. 1998 Jan 22;391(6665):401-4 PMID: 9450758
  26. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo.
    Cancer Res. 1999 Aug 1;59(15):3547-51 PMID: 10446958
  27. Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13.
    Oncogene. 1995 Apr 20;10(8):1673-5 PMID: 7731724
  28. Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair.
    Mol Cell. 1998 Jul;2(1):9-22 PMID: 9702187
  29. Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants.
    Nat Genet. 1999 Sep;23(1):81-5 PMID: 10471504
  30. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification.
    Curr Biol. 1999 Oct 7;9(19):1107-10 PMID: 10531007
  31. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V.
    J Immunol Methods. 1995 Jul 17;184(1):39-51 PMID: 7622868
  32. Association of BRCA1 with Rad51 in mitotic and meiotic cells.
    Cell. 1997 Jan 24;88(2):265-75 PMID: 9008167
  33. Isolation and cross-sensitivity of X-ray-sensitive mutants of V79-4 hamster cells.
    Mutat Res. 1987 May;183(3):279-86 PMID: 3106801
  34. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation.
    EMBO J. 1993 Sep;12(9):3679-84 PMID: 8253089
  35. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.
    Science. 1999 Jul 30;285(5428):747-50 PMID: 10426999
  36. The multistep nature of cancer.
    Trends Genet. 1993 Apr;9(4):138-41 PMID: 8516849
  37. Classification and relationships of induced chromosomal structual changes.
    J Med Genet. 1976 Apr;13(2):103-22 PMID: 933108
  38. Lack of chromosome territoriality in yeast: promiscuous rejoining of broken chromosome ends.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13949-54 PMID: 8943041
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
Published
2000-06-01
Pages
1400-6
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316655
Subset
IM
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2