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

Abstract

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.

• Authors: José F Ruiz, Belén Gómez-González, Andrés Aguilera
• Journal: PLoS genetics (PLoS Genet) Vol. 7 Issue 2 Pg. e1002009 (Feb 2011) ISSN: 1553-7404 [Electronic] United States
• PMID: 21383964 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-myc
• AICDA (activation-induced cytidine deaminase)
• Cytidine Deaminase

Topics

• Animals
• Base Sequence
• Chromosomes, Fungal
• Cytidine Deaminase (genetics, metabolism)
• DNA Breaks, Double-Stranded
• Humans
• Immunoglobulin Switch Region
• Mice
• Molecular Sequence Data
• Mutation
• Proto-Oncogene Proteins c-myc (genetics)
• Recombination, Genetic
• Saccharomyces cerevisiae (enzymology, genetics)
• Sequence Alignment
• Translocation, Genetic