This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stark, J. M.
Right arrow Articles by Jasin, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stark, J. M.
Right arrow Articles by Jasin, M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2003, p. 733-743, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.733-743.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Extensive Loss of Heterozygosity Is Suppressed during Homologous Repair of Chromosomal Breaks

Jeremy M. Stark and Maria Jasin*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, New York 10021

Received 4 September 2002/ Returned for modification 14 October 2002/ Accepted 24 October 2002

Loss of heterozygosity (LOH) is a common genetic alteration in tumors and often extends several megabases to encompass multiple genetic loci or even whole chromosome arms. Based on marker and karyotype analysis of tumor samples, a significant fraction of LOH events appears to arise from mitotic recombination between homologous chromosomes, reminiscent of recombination during meiosis. As DNA double-strand breaks (DSBs) initiate meiotic recombination, a potential mechanism leading to LOH in mitotically dividing cells is DSB repair involving homologous chromosomes. We therefore sought to characterize the extent of LOH arising from DSB-induced recombination between homologous chromosomes in mammalian cells. To this end, a recombination reporter was introduced into a mouse embryonic stem cell line that has nonisogenic maternal and paternal chromosomes, as is the case in human populations, and then a DSB was introduced into one of the chromosomes. Recombinants involving alleles on homologous chromosomes were readily obtained at a frequency of 4.6 x 10-5; however, this frequency was substantially lower than that of DSB repair by nonhomologous end joining or the inferred frequency of homologous repair involving sister chromatids. Strikingly, the majority of recombinants had LOH restricted to the site of the DSB, with a minor class of recombinants having LOH that extended to markers 6 kb from the DSB. Furthermore, we found no evidence of LOH extending to markers 1 centimorgan or more from the DSB. In addition, crossing over, which can lead to LOH of a whole chromosome arm, was not observed, implying that there are key differences between mitotic and meiotic recombination mechanisms. These results indicate that extensive LOH is normally suppressed during DSB-induced allelic recombination in dividing mammalian cells.

* Corresponding author. Mailing address: Cell Biology Program, Memorial Sloan-Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, 1275 York Ave., New York, NY 10021. Phone (212) 639-7438. Fax: (212) 717-3317. E-mail: m-jasin{at}ski.mskcc.org.

Molecular and Cellular Biology, January 2003, p. 733-743, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.733-743.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Smith, C. E., Lam, A. F., Symington, L. S. (2009). Aberrant Double-Strand Break Repair Resulting in Half Crossovers in Mutants Defective for Rad51 or the DNA Polymerase {delta} Complex. Mol. Cell. Biol. 29: 1432-1441 [Abstract] [Full Text]  
  • Prakash, R., Satory, D., Dray, E., Papusha, A., Scheller, J., Kramer, W., Krejci, L., Klein, H., Haber, J. E., Sung, P., Ira, G. (2009). Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination. Genes Dev. 23: 67-79 [Abstract] [Full Text]  
  • Damaj, L., le Lorch, M., Verkarre, V., Werl, C., Hubert, L., Nihoul-Fekete, C., Aigrain, Y., de Keyzer, Y., Romana, S. P., Bellanne-Chantelot, C., de Lonlay, P., Jaubert, F. (2008). Chromosome 11p15 Paternal Isodisomy in Focal Forms of Neonatal Hyperinsulinism. J. Clin. Endocrinol. Metab. 93: 4941-4947 [Abstract] [Full Text]  
  • Deem, A., Barker, K., VanHulle, K., Downing, B., Vayl, A., Malkova, A. (2008). Defective Break-Induced Replication Leads to Half-Crossovers in Saccharomyces cerevisiae. Genetics 179: 1845-1860 [Abstract] [Full Text]  
  • Gorbunova, V., Seluanov, A., Mao, Z., Hine, C. (2007). Changes in DNA repair during aging. Nucleic Acids Res 35: 7466-7474 [Abstract] [Full Text]  
  • Hu, Y., Raynard, S., Sehorn, M. G., Lu, X., Bussen, W., Zheng, L., Stark, J. M., Barnes, E. L., Chi, P., Janscak, P., Jasin, M., Vogel, H., Sung, P., Luo, G. (2007). RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. Genes Dev. 21: 3073-3084 [Abstract] [Full Text]  
  • Cullen, J. K., Hussey, S. P., Walker, C., Prudden, J., Wee, B.-Y., Dave, A., Findlay, J. S., Savory, A. P., Humphrey, T. C. (2007). Break-Induced Loss of Heterozygosity in Fission Yeast: Dual Roles for Homologous Recombination in Promoting Translocations and Preventing De Novo Telomere Addition. Mol. Cell. Biol. 27: 7745-7757 [Abstract] [Full Text]  
  • Neuwirth, E. A. H., Honma, M., Grosovsky, A. J. (2007). Interchromosomal Crossover in Human Cells Is Associated with Long Gene Conversion Tracts. Mol. Cell. Biol. 27: 5261-5274 [Abstract] [Full Text]  
  • Pfeifer, D., Pantic, M., Skatulla, I., Rawluk, J., Kreutz, C., Martens, U. M., Fisch, P., Timmer, J., Veelken, H. (2007). Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays. Blood 109: 1202-1210 [Abstract] [Full Text]  
  • Ira, G., Satory, D., Haber, J. E. (2006). Conservative Inheritance of Newly Synthesized DNA in Double-Strand Break-Induced Gene Conversion. Mol. Cell. Biol. 26: 9424-9429 [Abstract] [Full Text]  
  • Nagaraju, G., Odate, S., Xie, A., Scully, R. (2006). Differential Regulation of Short- and Long-Tract Gene Conversion between Sister Chromatids by Rad51C. Mol. Cell. Biol. 26: 8075-8086 [Abstract] [Full Text]  
  • Weinstock, D. M., Jasin, M. (2006). Alternative Pathways for the Repair of RAG-Induced DNA Breaks. Mol. Cell. Biol. 26: 131-139 [Abstract] [Full Text]  
  • Gruver, A. M., Miller, K. A., Rajesh, C., Smiraldo, P. G., Kaliyaperumal, S., Balder, R., Stiles, K. M., Albala, J. S., Pittman, D. L. (2005). The ATPase motif in RAD51D is required for resistance to DNA interstrand crosslinking agents and interaction with RAD51C. Mutagenesis 20: 433-440 [Abstract] [Full Text]  
  • Nakanishi, K., Yang, Y.-G., Pierce, A. J., Taniguchi, T., Digweed, M., D'Andrea, A. D., Wang, Z.-Q., Jasin, M. (2005). Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc. Natl. Acad. Sci. USA 102: 1110-1115 [Abstract] [Full Text]  
  • Stark, J. M., Pierce, A. J., Oh, J., Pastink, A., Jasin, M. (2004). Genetic Steps of Mammalian Homologous Repair with Distinct Mutagenic Consequences. Mol. Cell. Biol. 24: 9305-9316 [Abstract] [Full Text]  
  • Smirnova, M., Van Komen, S., Sung, P., Klein, H. L. (2004). Effects of Tumor-associated Mutations on Rad54 Functions. J. Biol. Chem. 279: 24081-24088 [Abstract] [Full Text]  
  • Rong, Y. S., Golic, K. G. (2003). The Homologous Chromosome Is an Effective Template for the Repair of Mitotic DNA Double-Strand Breaks in Drosophila. Genetics 165: 1831-1842 [Abstract] [Full Text]  
  • Onclercq-Delic, R., Calsou, P., Delteil, C., Salles, B., Papadopoulo, D., Amor-Gueret, M. (2003). Possible anti-recombinogenic role of Bloom's syndrome helicase in double-strand break processing. Nucleic Acids Res 31: 6272-6282 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»