Homologous, homeologous, and illegitimate repair of double-strand breaks during transformation of a wild-type strain and a rad52 mutant strain of Saccharomyces cerevisiae.

Mézard, Christine; Nicolas, Alain

doi:10.1128/mcb.14.2.1278

Cited by 72 publications

(53 citation statements)

References 70 publications

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“…Recombination events promoted by very small stretches of homology have been described for experimental systems 23 and for mutations leading to human disease. 24,25 The sequence CTGGT occurs once in intron 3 and twice in intron 7.…”

Section: Discussionmentioning

confidence: 99%

Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II

et al. 1998

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About 20% of patients with mucopolysaccharidosis type II (MPS II) have gross structural rearrangements involving the iduronate-sulfatase (IDS) gene in Xq27.3-q28. A nearby IDS pseudogene (IDS-2) promotes nonallelic recombination between highly homologous sequences. Here we describe major rearrangements due to gene/pseudogene recombination. In two unrelated patients, partial IDS gene deletions were found joining introns 3 and 7 of the IDS gene together with gene to pseudogene conversion in the area of breakpoints. In a third patient, a junction between intron 3 of IDS-2 and intron 7 of IDS was seen that was due to a deletion and inversion of the 5' part of the gene. Characterisation of breakpoints in six patients with large inversions revealed that all recombinations of this type occurred in the same area of homology between IDS and IDS-2; they were molecularly balanced, and accompanied by gene conversions in most cases. Apart from diagnostic implications, such naturally occurring recombination 'hot spots' may allow some insight into general features of crossover events in mammals.

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Section: Discussionmentioning

confidence: 99%

Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II

et al. 1998

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“…In Saccharomyces cerevisiae, efficient DNA repair by SSA requires a minimum of 60 to 90 bp of perfect homology in the regions flanking the DSB (57). A similar intermediate might occur in nonhomologous end joining (NHEJ), although only 1 to 5 bp of precise homology is sufficient for end joining in S. cerevisiae (29,33,34). This might explain why these nonhomologous events occur 1 to 2 orders of magnitude less frequently than SSA.…”

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confidence: 99%

“…Endjoining reactions also differ from classical homologous recombination in that they are typically nonconservative, such that the joining process results in a loss or gain in nucleotide base number (41,46). End joining in a wide array of organisms has been studied, from higher eucaryotes (14, 30,41,47) or simple eucaryotes (13,29,33,34,53,54,60) to bacteria (7,27). Even though the systems and the methods used to study end joining vary, the joint molecules formed are strikingly similar.…”

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confidence: 99%

Cell Cycle and Genetic Requirements of Two Pathways of Nonhomologous End-Joining Repair of Double-Strand Breaks in Saccharomyces cerevisiae

Moore

Haber

1996

Molecular and Cellular Biology

691

587

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In Saccharomyces cerevisiae, an HO endonuclease-induced double-strand break can be repaired by at least two pathways of nonhomologous end joining (NHEJ) that closely resemble events in mammalian cells. In one pathway the chromosome ends are degraded to yield deletions with different sizes whose endpoints have 1 to 6 bp of homology. Alternatively, the 4-bp overhanging 3 ends of HO-cut DNA (5-AACA-3) are not degraded but can be base paired in misalignment to produce ؉CA and ؉ACA insertions. When HO was expressed throughout the cell cycle, the efficiency of NHEJ repair was 30 times higher than when HO was expressed only in G 1 . The types of repair events were also very different when HO was expressed throughout the cell cycle; 78% of survivors had small insertions, while almost none had large deletions. When HO expression was confined to the G 1 phase, only 21% were insertions and 38% had large deletions. These results suggest that there are distinct mechanisms of NHEJ repair producing either insertions or deletions and that these two pathways are differently affected by the time in the cell cycle when HO is expressed. The frequency of NHEJ is unaltered in strains from which RAD1, RAD2, RAD51, RAD52, RAD54, or RAD57 is deleted; however, deletions of RAD50, XRS2, or MRE11 reduced NHEJ by more than 70-fold when HO was not cell cycle regulated. Moreover, mutations in these three genes markedly reduced ؉CA insertions, while significantly increasing the proportion of both small (؊ACA) and larger deletion events. In contrast, the rad50 mutation had little effect on the viability of G 1 -induced cells but significantly reduced the frequency of both ؉CA insertions and ؊ACA deletions in favor of larger deletions. Thus, RAD50 (and by extension XRS2 and MRE11) exerts a much more important role in the insertion-producing pathway of NHEJ repair found in S and/or G 2 than in the less frequent deletion events that predominate when HO is expressed only in G 1 .

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“…Numerous studies of S. cerevisiae have been done to address the effect of sequence heterogeneity on mitotic recombination rates (5,15,23,31,32,42,51,56), and several of these have investigated the possible involvement of the yeast mismatch repair machinery in regulating homeologous interactions (4,5,42,56). These studies used substrates with less than 85% homology, and while all found at least a 15-fold effect of sequence divergence on recombination rates in wild-type strains, the magnitude of the effect was quite variable.…”

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confidence: 99%

Mitotic Crossovers between Diverged Sequences Are Regulated by Mismatch Repair Proteins in Saccharomyces cerevisiae

Datta

Adjiri

New

et al. 1996

Molecular and Cellular Biology

204

192

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Mismatch repair systems correct replication-and recombination-associated mispaired bases and influence the stability of simple repeats. These systems thus serve multiple roles in maintaining genetic stability in eukaryotes, and human mismatch repair defects have been associated with hereditary predisposition to cancer. In prokaryotes, mismatch repair systems also have been shown to limit recombination between diverged (homeologous) sequences. We have developed a unique intron-based assay system to examine the effects of yeast mismatch repair genes (PMS1, MSH2, and MSH3) on crossovers between homeologous sequences. We find that the apparent antirecombination effects of mismatch repair proteins in mitosis are related to the degree of substrate divergence. Defects in mismatch repair can elevate homeologous recombination between 91% homologous substrates as much as 100-fold while having only modest effects on recombination between 77% homologous substrates. These observations have implications for genome stability and general mechanisms of recombination in eukaryotes.Much of our knowledge concerning the mechanism of homologous recombination in eukaryotes has come from studies done with the yeast Saccharomyces cerevisiae (for a review, see reference 40), in which two basic types of recombination occur: reciprocal recombination (crossing-over) and nonreciprocal recombination (gene conversion). Reciprocal recombination events involve the physical exchange of information between chromosomes and hence alter the genetic linkages of markers on either side of the crossover event. Gene conversion events involve the unidirectional transfer of information from one chromosome to another and are nonrandomly associated with crossing-over. The association between gene conversion and crossing-over has been central to developing molecular models of recombination in which conversion events reflect the formation of a heteroduplex intermediate that can be resolved in either a crossover or noncrossover mode (16,30,67). Homologous recombination is usually thought of as occurring between sequences at identical positions on homologous chromosomes (allelic recombination), but it also can involve similar sequences at nonallelic (ectopic) locations (for reviews, see references 20 and 39). A large number of repeated sequences are found dispersed throughout eukaryotic genomes and can serve as substrates for ectopic recombination events. Such repeats exhibit various degrees of homology at the DNA level and are referred to as being homeologous to reflect their partial homology. Ectopic gene conversion between homeologous sequences can lead to the homogenization of repeats and is likely to be an important mechanism for the concerted evolution of multigene families (12). It also can generate novel sequence combinations within a gene family and has been implicated as a possible source of diversity at immunoglobulin loci (6, 28). Crossing-over between dispersed repeats results in genome rearrangements (deletions, duplications, inversions, and translo...

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Homologous, homeologous, and illegitimate repair of double-strand breaks during transformation of a wild-type strain and a rad52 mutant strain of Saccharomyces cerevisiae.

Cited by 72 publications

References 70 publications

Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II

Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II

Cell Cycle and Genetic Requirements of Two Pathways of Nonhomologous End-Joining Repair of Double-Strand Breaks in Saccharomyces cerevisiae

Mitotic Crossovers between Diverged Sequences Are Regulated by Mismatch Repair Proteins in Saccharomyces cerevisiae

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