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Molecular and Cellular Biology, November 2007, p. 7745-7757, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00462-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Break-Induced Loss of Heterozygosity in Fission Yeast: Dual Roles for Homologous Recombination in Promoting Translocations and Preventing De Novo Telomere Addition{triangledown} ,{dagger}

Jason K. Cullen, Sharon P. Hussey, Carol Walker, John Prudden, Boon-Yu Wee, Anoushka Davé, James S. Findlay, Andrew P. Savory, and Timothy C. Humphrey*

MRC Radiation Oncology and Biology Unit, Harwell, Didcot, Oxfordshire OX11 0RD, United Kingdom

Received 17 March 2007/ Returned for modification 6 April 2007/ Accepted 14 July 2007

Loss of heterozygosity (LOH), a causal event in tumorigenesis, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms leading to such extensive LOH are poorly understood. We investigated the mechanisms of DNA double-strand break (DSB)-induced extensive LOH by screening for auxotrophic marker loss ~25 kb distal to an HO endonuclease break site within a nonessential minichromosome in Schizosaccharomyces pombe. Extensive break-induced LOH was infrequent, resulting from large translocations through both allelic crossovers and break-induced replication. These events required the homologous recombination (HR) genes rad32+, rad50+, nbs1+, rhp51+, rad22+, rhp55+, rhp54+, and mus81+. Surprisingly, LOH was still observed in HR mutants, which resulted predominantly from de novo telomere addition at the break site. De novo telomere addition was most frequently observed in rad22{Delta} and rhp55{Delta} backgrounds, which disrupt HR following end resection. Further, levels of de novo telomere addition, while increased in ku70{Delta} rhp55{Delta} strains, were reduced in exo1{Delta} rhp55{Delta} and an rhp55{Delta} strain overexpressing rhp51. These findings support a model in which HR prevents de novo telomere addition at DSBs by competing for resected ends. Together, these results suggest that the mechanisms of break-induced LOH may be predicted from the functional status of the HR machinery.

* Corresponding author. Mailing address: MRC Radiation Oncology and Biology Unit, Harwell, Didcot, Oxfordshire OX11 0RD, United Kingdom. Phone: 44 (0) 1235 841114. Fax: 44 (0) 1235 841200. E-mail: T.Humphrey{at}har.mrc.ac.uk

{triangledown} Published ahead of print on 27 August 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2007, p. 7745-7757, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00462-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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