Title:

Gross chromosomal rearrangements in the centromere

 

Takuro Nakagawa
Graduate School of Science, Osaka University

 

Abstract:
Centromeres consist of unique DNA repeats in many eukaryotes [1]. Gross chromosomal rearrangements (GCRs) between them can result in the formation of abnormal chromosomes such as Robertsonian translocations and isochromosomes in which both arms are identical and mirror images. An increasing body of evidence shows that GCRs mediated by non-allelic homologous recombination (HR) between repeats cause various types of genetic disorder in humans [2]. However, how GCRs occur and how they are suppressed in cells remain largely unknown.
Previously, we found that Rad51 suppresses isochromosome formation in the centromere region of the fission yeast Schizosaccharomyces pombe [3]. However, how the key player of HR prevents homology-mediated GCRs remains unclear. I am going to present our recent data showing that Rad51 with the aid of Rad54 a Swi/Snf-type of motor protein promotes noncrossover recombination between centromere repeats, thereby preventing crossover recombination that results in isochromosome formation. We found that mutations in Rad51 and Rad54 increased isochromosome formation but abolished noncrossover recombination between inverted repeats in the centromere. In the rad51 deletion background, deletion of Mus81 a crossover-specific endonuclease decreased the GCR rate. Rad8 the homolog of mammalian HLTF that is involved in template switching, was also required for GCRs in the absence of Rad51. Therefore, I propose a model in which homology-mediated GCRs occur through formation of joint molecules by Rad8 and their cleavage by Mus81 resolvase.

 

References:
1. Allshire, R.C., and Karpen, G.H. (2008). Epigenetic regulation of centromeric chromatin: old dogs, new tricks? Nat Rev Genet 9, 923-937.
2. Stankiewicz, P., and Lupski, J.R. (2002). Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74-82.
3. Nakamura, K., Okamoto, A., Katou, Y., Yadani, C., Shitanda, T., Kaweeteerawat, C., Takahashi, T.S., Itoh, T., Shirahige, K., Masukata, H., et al. (2008). Rad51 suppresses gross chromosomal rearrangement at centromere in Schizosaccharomyces pombe. EMBO J. 27, 3036-3046.