Abstract
BackgroundThe presence of inverted repeats (IRs) in DNA poses an obstacle to the normal progression of the DNA replication machinery, because these sequences can form secondary structures ahead of the replication fork. A failure to process and to restart the stalled replication machinery can lead to the loss of genome integrity. Consistently, IRs have been found to be associated with a high level of genome rearrangements, including deletions, translocations, inversions, and a high rate of sister-chromatid exchange (SCE). The RecQ helicase Sgs1, in Saccharomyces cerevisiae, is believed to act on stalled replication forks. To determine the role of Sgs1 when the replication machinery stalls at the secondary structure, we measured the rates of IR-associated and non-IR-associated spontaneous unequal SCE events in the sgs1 mutant, and in strains bearing mutations in genes that are functionally related to SGS1.ResultsThe rate of SCE in sgs1 cells for both IR and non-IR-containing substrates was higher than the rate in the wild-type background. The srs2 and mus81 mutations had modest effects, compared to sgs1. The exo1 mutation increased SCE rates for both substrates. The sgs1 exo1 double mutant exhibited synergistic effects on spontaneous SCE. The IR-associated SCE events in sgs1 cells were partially MSH2-dependent.ConclusionsThese results suggest that Sgs1 suppresses spontaneous unequal SCE, and SGS1 and EXO1 regulate spontaneous SCE by independent mechanisms. The mismatch repair proteins, in contradistinction to their roles in mutation avoidance, promote secondary structure-associated genetic instability.
Highlights
The presence of inverted repeats (IRs) in DNA poses an obstacle to the normal progression of the DNA replication machinery, because these sequences can form secondary structures ahead of the replication fork
The sgs1 mutation increases the rates of spontaneous unequal sister-chromatid exchange (SCE) of both the non-IR-containing and IRcontaining substrates, whereas the srs2 and mus81 mutations produce much smaller effects Recombination between sister chromatids occurs spontaneously, and the majority of these recombination events are likely to occur during DNA replication
Since a secondary structure is likely to act as an obstacle to the progression of the replication fork, DNA sequence elements that have the potential to form secondary structures have been shown to compromise DNA replication both in vivo and in vitro [40,41,42,43,44]
Summary
The presence of inverted repeats (IRs) in DNA poses an obstacle to the normal progression of the DNA replication machinery, because these sequences can form secondary structures ahead of the replication fork. A failure to process and to restart the stalled replication machinery can lead to the loss of genome integrity. During DNA replication, the extension of daughter strands is continuously impaired by a number of factors, such as proteins bound to the template, endogenously or exogenously induced DNA damage, and the presence of DNA secondary structures. BMC Molecular Biology 2007, 8:120 http://www.biomedcentral.com/1471-2199/8/120 the replication-associated lesions, and to restart the stalled fork, will lead to chromosome loss or impairment of the integrity of the genome. Maintenance of the stability of the genome is critical for normal cell growth and cell viability
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