Genome-wide screen reveals replication pathway for quasi-palindrome fragility dependent on homologous recombination

Inverted repeats capable of forming hairpin and cruciform structures present a threat to chromosomal integrity. They induce double strand breaks, which lead to gross chromosomal rearrangements, the hallmarks of cancers and hereditary diseases. Secondary structure formation at this motif has been pro...

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Bibliographic Details
Published in:PLoS genetics 2013-12, Vol.9 (12), p.e1003979-e1003979
Main Authors: Zhang, Yu, Saini, Natalie, Sheng, Ziwei, Lobachev, Kirill S
Format: Article
Language:English
Subjects:
Alu Elements - genetics
Chromosome Fragility - genetics
Chromosomes
Confidence intervals
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA replication
DNA Replication - genetics
E coli
Experiments
Gene amplification
Genetic disorders
Genetic recombination
Genome, Fungal - genetics
Genome-wide association studies
Genomes
Genomics
Homologous Recombination - genetics
Inverted Repeat Sequences - genetics
Nucleic Acid Conformation
Nucleotide Motifs - genetics
Proteins
Rad51 Recombinase - genetics
Saccharomyces cerevisiae - genetics
Standard deviation
Yeast
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Summary:Inverted repeats capable of forming hairpin and cruciform structures present a threat to chromosomal integrity. They induce double strand breaks, which lead to gross chromosomal rearrangements, the hallmarks of cancers and hereditary diseases. Secondary structure formation at this motif has been proposed to be the driving force for the instability, albeit the mechanisms leading to the fragility are not well-understood. We carried out a genome-wide screen to uncover the genetic players that govern fragility of homologous and homeologous Alu quasi-palindromes in the yeast Saccharomyces cerevisiae. We found that depletion or lack of components of the DNA replication machinery, proteins involved in Fe-S cluster biogenesis, the replication-pausing checkpoint pathway, the telomere maintenance complex or the Sgs1-Top3-Rmi1 dissolvasome augment fragility at Alu-IRs. Rad51, a component of the homologous recombination pathway, was found to be required for replication arrest and breakage at the repeats specifically in replication-deficient strains. These data demonstrate that Rad51 is required for the formation of breakage-prone secondary structures in situations when replication is compromised while another mechanism operates in DSB formation in replication-proficient strains.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1003979