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Molecular and Cellular Biology, January 2002, p. 669-679, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.669-679.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Brca2 (XRCC11) Deficiency Results in Radioresistant DNA Synthesis and a Higher Frequency of Spontaneous Deletions

Maria Kraakman-van der Zwet,1,2 Wilhelmina J. I. Overkamp,1,{dagger} Rebecca E. E. van Lange,1 Jeroen Essers,3 Annemarie van Duijn-Goedhart,1,2 Ingrid Wiggers,1 Srividya Swaminathan,4 Paul P. W. van Buul,1,2 Abdellatif Errami,1,2 Raoul T. L. Tan,3 Nicolaas G. J. Jaspers,3 Shyam K. Sharan,4 Roland Kanaar,3,5 and Malgorzata Z. Zdzienicka1,2*

Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Center,1 J. A. Cohen Institute, Interuniversity Research Institute for Radiopathology and Radiation Protection, Leiden,2 Department of Cell Biology and Genetics-MGC, Erasmus University,3 Mouse Cancer Genetics Program, National Cancer Institute-FCRDC, Frederick, Maryland,4 Department of Radiation Oncology, University Hospital Rotterdam/Daniel, Rotterdam, The Netherlands5

Received 11 June 2001/ Returned for modification 21 July 2001/ Accepted 8 October 2001

We show here that the radiosensitive Chinese hamster cell mutant (V-C8) of group XRCC11 is defective in the breast cancer susceptibility gene Brca2. The very complex phenotype of V-C8 cells is complemented by a single human chromosome 13 providing the BRCA2 gene, as well as by the murine Brca2 gene. The Brca2 deficiency in V-C8 cells causes hypersensitivity to various DNA-damaging agents with an extreme sensitivity toward interstrand DNA cross-linking agents. Furthermore, V-C8 cells show radioresistant DNA synthesis after ionizing radiation, suggesting that Brca2 deficiency affects cell cycle checkpoint regulation. In addition, V-C8 cells display tremendous chromosomal instability and a high frequency of abnormal centrosomes. The mutation spectrum at the hprt locus showed that the majority of spontaneous mutations in V-C8 cells are deletions, in contrast to wild-type V79 cells. A mechanistic explanation for the genome instability phenotype of Brca2-deficient cells is provided by the observation that the nuclear localization of the central DNA repair protein in homologous recombination, Rad51, is reduced in V-C8 cells.

* Corresponding author. Mailing address: Department of Radiation Genetics and Chemical Mutagenesis-MGC, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. Phone: 31-71-527-6175. Fax: 31-71-527-6173. E-mail: m.z.zdzienicka{at}lumc.nl.

{dagger} Deceased.

Molecular and Cellular Biology, January 2002, p. 669-679, Vol. 22, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.2.669-679.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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