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Rad51 overexpression promotes alternative double-strand break repair pathways and genome instability

Oncogene volume 23, pages 546–553 (2004)Cite this article

Abstract

Genomic instability is characteristic of tumor cells, and a strong correlation exists between abnormal karyotype and tumorigenicity. Increased expression of the homologous recombination and DNA repair protein Rad51 has been reported in immortalized and tumor cells, which could alter recombination pathways to contribute to the chromosomal rearrangements found in these cells. We used a genetic system to examine the potential for multiple double-strand breaks to lead to genome rearrangements in the presence of increased Rad51 expression. Analysis of repair revealed a novel class of products consistent with crossing over, involving gene conversion associated with an exchange of flanking markers leading to chromosomal translocations. Increased Rad51 also promoted aneuploidy and multiple chromosomal rearrangements. These data provide a link between elevated Rad51 protein levels, genome instability, and tumor progression.

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Abbreviations

DSB:

DNA double-strand break

ES:

embryonic stem

STGC:

short-tract gene conversion

LTGC:

long-tract gene conversion

NHEJ:

nonhomologous endjoining

chr.14:

chromosome 14

chr.17:

chromosome 17

FISH:

fluorescence in situ hybridization

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Acknowledgements

We thank Ramon Parsons and Hein te Riele for materials, Jac Nickoloff for helpful comments, Murty Vundivalli for metaphase preparations and SKY analysis, Vladin Miljkovic for sequencing, and Teresa Swayne for assistance with FISH analysis (Columbia University microscopy facility established and supported by N.I.H. grants S10 RR10506, S10 RR13701, and P30 CA13696). This work was supported in part by a Leukemia and Lymphoma fellowship to CR. JS is supported by an American Cancer Society post-doctoral fellowship PF-00-106-01-MGO. This work was supported by a National Science Foundation grant MCB-9728333 to MJ.

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Authors and Affiliations

  1. Department of Pathology, Institute of Cancer Genetics, Columbia University College of Physicians and Surgeons, 1150 St Nicholas Avenue, New York, 10032, NY, USA

    Christine Richardson & Melissa Ommundsen

  2. Cell Biology Program, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, 1275 York Avenue, New York, 10021, NY, USA

    Christine Richardson, Jeremy M Stark & Maria Jasin

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  1. Christine Richardson
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Correspondence to Christine Richardson.

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Richardson, C., Stark, J., Ommundsen, M. et al. Rad51 overexpression promotes alternative double-strand break repair pathways and genome instability. Oncogene 23, 546–553 (2004). https://doi.org/10.1038/sj.onc.1207098

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