AID induces double-strand breaks at immunoglobulin switch regions and c-MYC causing chromosomal translocations in yeast THO mutants

Transcription of the switch (s) regions of immunoglobulin genes in b cells generates stable r-loops that are targeted by activation induced cytidine deaminase (aid),triggering class switch recombination (csr),as well as translocations with c-myc responsible for burkitt's lymphomas. in saccharomyces cerevisiae,stable r-loops are formed co-transcriptionally in mutants of tho,a conserved nuclear complex involved in mrnp biogenesis. such r-loops trigger genome instability and facilitate deamination by human aid. to understand the mechanisms that generate genome instability mediated by mrnp biogenesis impairment and by aid,we devised a yeast chromosomal system based on different segments of mammalian s regions and c-myc for the analysis of chromosomal rearrangements in both wild-type and tho mutants. we demonstrate that aid acts in yeast at heterologous s and c-myc transcribed sequences leading to double-strand breaks (dsbs) which in turn cause chromosomal translocations via non-homologous end joining (nhej). aid-induced translocations were strongly enhanced in yeast tho null mutants,consistent with the idea that aid-mediated dsbs depend on r-loop formation. our study not only provides new clues to understand the role of mrnp biogenesis in preventing genome rearrangements and the mechanism of aid-mediated genome instability,but also shows that,once uracil residues are produced by aid-mediated deamination,these are processed into dsbs and chromosomal rearrangements by the general and conserved dna repair functions present from yeast to human cells. © 2011 ruiz et al.