The Contribution of Alu Elements to Mutagenic DNA Double-Strand Break Repair


DNA double-strand breaks (DSBs) are a highly mutagenic form of DNA damage that can be repaired through one of several pathways with varied degrees of sequence preservation. Faithful repair of DSBs often occurs through gene conversion in which a sister chromatid is used as a repair template. Unfaithful repair of DSBs can occur through non-allelic homologous or homeologous recombination, which leads to chromosomal abnormalities such as deletions, duplications, and translocations and has been shown to cause several human genetic diseases. Substrates for these homologous and homeologous events include Alu elements, which are approximately 300 bp elements that comprise ~11% of the human genome. We use a new reporter assay to show that repair of DSBs results in Alu-mediated deletions that resolve through several distinct repair pathways. Either single-strand annealing (SSA) repair or microhomology-mediated end joining occurs ‘in register’ between two Alu elements when Alu sequence divergence is low. However, with more diverged Alu elements, like those typically found in the human genome, repair of DSBs appears to use the Alu/Alu homeology to direct non-homologous end joining in the general vicinity of the Alu elements. Mutagenic NHEJ repair involving divergent Alu elements may represent a common repair event in primate genomes.


Vyšlo v časopise: The Contribution of Alu Elements to Mutagenic DNA Double-Strand Break Repair. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005016
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005016

Souhrn

DNA double-strand breaks (DSBs) are a highly mutagenic form of DNA damage that can be repaired through one of several pathways with varied degrees of sequence preservation. Faithful repair of DSBs often occurs through gene conversion in which a sister chromatid is used as a repair template. Unfaithful repair of DSBs can occur through non-allelic homologous or homeologous recombination, which leads to chromosomal abnormalities such as deletions, duplications, and translocations and has been shown to cause several human genetic diseases. Substrates for these homologous and homeologous events include Alu elements, which are approximately 300 bp elements that comprise ~11% of the human genome. We use a new reporter assay to show that repair of DSBs results in Alu-mediated deletions that resolve through several distinct repair pathways. Either single-strand annealing (SSA) repair or microhomology-mediated end joining occurs ‘in register’ between two Alu elements when Alu sequence divergence is low. However, with more diverged Alu elements, like those typically found in the human genome, repair of DSBs appears to use the Alu/Alu homeology to direct non-homologous end joining in the general vicinity of the Alu elements. Mutagenic NHEJ repair involving divergent Alu elements may represent a common repair event in primate genomes.


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