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Molecular and Cellular Biology, September 2006, p. 6675-6689, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00649-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Complex Minisatellite Rearrangements Generated in the Total or Partial Absence of Rad27/hFEN1 Activity Occur in a Single Generation and Are Rad51 and Rad52 Dependent{dagger}

Judith Lopes,{ddagger} Cyril Ribeyre,{ddagger} and Alain Nicolas*

Recombinaison et Instabilité Génétique, Institut Curie Centre de Recherche, UMR7147 CNRS Université Pierre et Marie Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France

Received 14 April 2006/ Returned for modification 5 June 2006/ Accepted 13 June 2006

Genomes contain tandem repeat blocks that are at risk of expansion or contraction. The mechanisms of destabilization of the human minisatellite CEB1 (arrays of 36- to 43-bp repeats) were investigated in a previously developed model system, in which CEB1-0.6 (14 repeats) and CEB1-1.8 (42 repeats) alleles were inserted into the genome of Saccharomyces cerevisiae. As in human cells, CEB1 is stable in mitotically growing yeast cells but is frequently rearranged in the absence of the Rad27/hFEN1 protein involved in Okazaki fragments maturation. To gain insight into this mode of destabilization, the CEB1-1.8 and CEB1-0.6 human alleles and 47 rearrangements derived from a CEB1-1.8 progenitor in rad27{Delta} cells were sequenced. A high degree of polymorphism of CEB1 internal repeats was observed, attesting to a large variety of homology-driven rearrangements. Simple deletion, double deletion, and highly complex events were observed. Pedigree analysis showed that all rearrangements, even the most complex, occurred in a single generation and were inherited equally by mother and daughter cells. Finally, the rearrangement frequency was found to increase with array size, and partial complementation of the rad27{Delta} mutation by hFEN1 demonstrated that the production of novel CEB1 alleles is Rad52 and Rad51 dependent. Instability can be explained by an accumulation of unresolved flap structures during replication, leading to the formation of recombinogenic lesions and faulty repair, best understood by homology-dependent synthesis-strand displacement and annealing.

* Corresponding author. Mailing address: Recombinaison et Instabilité Génétique, Institut Curie Centre de Recherche, UMR7147 CNRS UPMC, 26 rue d'Ulm, 75248 Paris Cedex 05, France. Phone: 33 (0) 1 42 34 65 20. Fax: 33 (0) 1 42 34 66 44. E-mail: alain.nicolas{at}curie.fr.

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

{ddagger} J.L. and C.R. contributed equally to this work.

Molecular and Cellular Biology, September 2006, p. 6675-6689, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00649-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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