Interaction of Genetic and Environmental Factors in Saccharomyces cerevisiae Meiosis: The Devil is in the Details

Cotton, Victoria E.; Hoffmann, Eva R.; Abdullah, Mohamad Faiz Foong; Borts, Rhona H.

doi:10.1007/978-1-59745-527-5_1

Cited by 21 publications

(14 citation statements)

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“…48,49 The correlative genomic analysis presented here cannot distinguish between these possibilities. However, the previously documented spatial correlation between these two aspects of promoter behavior-H3K4me3 enrichment and preferential DSB formation-should no longer be viewed as providing strong evidence for a functional connection.…”

Section: Discussionmentioning

confidence: 85%

Scale matters

Tischfield

Keeney

2012

Cell Cycle

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During meiosis in many organisms, homologous chromosomes engage in numerous recombination events initiated by DNA double-strand breaks (DSBs) formed by the Spo11 protein. DSBs are distributed nonrandomly, which governs how recombination influences inheritance and genome evolution. The chromosomal features that shape DSB distribution are not well understood. In the budding yeast Saccharomyces cerevisiae, trimethylation of lysine 4 of histone H3 (H3K4me3) has been suggested to play a causal role in targeting Spo11 activity to small regions of preferred DSB formation called hotspots. The link between H3K4me3 and DSBs is supported in part by a genome-wide spatial correlation between the two. However, this correlation has only been evaluated using relatively low-resolution maps of DSBs, H3K4me3 or both. These maps illuminate chromosomal features that influence DSB distributions on a large scale (several kb and greater) but do not adequately resolve features, such as chromatin structure, that act on finer scales (kb and shorter). Using recent nucleotide-resolution maps of DSBs and meiotic chromatin structure, we find that the previously described spatial correlation between H3K4me3 and DSB hotspots is principally attributable to coincident localization of both to gene promoters. Once proximity to the nucleosome-depleted regions in promoters is accounted for, H3K4me3 status has only modest predictive power for determining DSB frequency or location. This analysis provides a cautionary tale about the importance of scale in genome-wide analyses of DSB and recombination patterns.

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Section: Discussionmentioning

confidence: 85%

Scale matters

Tischfield

Keeney

2012

Cell Cycle

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“…We have no explanation for these discrepancies other than to note that the strains are different as are the specifics of the sporulation procedures (Cotton et al 2009). MLH1 and MLH3 contribute equally to crossing over during meiosis: ATP hydrolysis by either Mlh1p (Hoffmann et al 2003) or Mlh3p alone appears to be sufficient for their function during meiotic recombination.…”

Section: Discussionmentioning

confidence: 92%

Distinct Regulation of Mlh1p Heterodimers in Meiosis and Mitosis in Saccharomyces cerevisiae

2010

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Mlh1p forms three heterodimers that are important for mismatch repair (Mlh1p/Pms1p), crossing over during meiosis (Mlh1p/Mlh3p), and channeling crossover events into a specific pathway (Mlh1p/Mlh2p). All four proteins contain highly conserved ATPase domains and Pms1p has endonuclease activity. Studies of the functional requirements for Mlh1p/Pms1p in Saccharomyces cerevisae revealed an asymmetric contribution of the ATPase domains to repairing mismatches. Here we investigate the functional requirements of the Mlh1p and Mlh3p ATPase domains in meiosis by constructing separation of function mutations in Mlh3p. These mutations are analogous to mutations of Mlh1p that have been shown to lead to loss of ATP binding and/or ATP hydrolysis. Our data suggest that ATP binding by Mlh3p is required for meiotic crossing over while ATP hydrolysis is dispensable. This has been seen previously for Mlh1p. However, when mutations that affect ATP hydrolysis by both Mlh3p and Mlh1p are combined within a single cell, meiotic crossover frequencies are reduced. These observations suggest that the function of the Mlh1p/Mlh3p heterodimer requires both subunits to bind ATP but only one to efficiently hydrolyze it. Additionally, two different amino acid substitutions to the same residue (G97) in Mlh3p affect the minor mismatch repair function of Mlh3p while only one of them compromises its ability to promote crossing over. These studies thus reveal different functional requirements among the heterodimers formed by Mlh1p.

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“…One possibility is that each TF mutant causes changes in cell physiology that, by crosstalk between transcriptional regulation networks, alter DSB activity at numerous gene promoters genome-wide via changes in local chromatin structure or loop-axis architecture. In this context, it is noteworthy that recombination distributions can be altered by auxotrophies for certain amino acids or nucleobases, including auxotrophies caused by mutation of several of the genes whose expression is known to be Bas1 dependent, such as HIS4 and ADE1 (Abdullah and Borts 2001;Cotton et al 2009). We found no correlation between DSB changes and gene expression changes in bas1 and ino4 mutants, but it remains possible that chromatin and higher order chromosome structure in and around the indirectly changed hotspots is affected.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Global Analysis of the Influences of Bas1 and Ino4 Transcription Factors on Meiotic DNA Break Distributions in Saccharomyces cerevisiae

Zhu

Keeney

2015

Genetics

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Meiotic recombination initiates with DNA double-strand breaks (DSBs) made by Spo11. In Saccharomyces cerevisiae, many DSBs occur in "hotspots" coinciding with nucleosome-depleted gene promoters. Transcription factors (TFs) stimulate DSB formation in some hotspots, but TF roles are complex and variable between locations. Until now, available data for TF effects on global DSB patterns were of low spatial resolution and confined to a single TF. Here, we examine at high resolution the contributions of two TFs to genome-wide DSB distributions: Bas1, which was known to regulate DSB activity at some loci, and Ino4, for which some binding sites were known to be within strong DSB hotspots. We examined fine-scale DSB distributions in TF mutant strains by deep sequencing oligonucleotides that remain covalently bound to Spo11 as a byproduct of DSB formation, mapped Bas1 and Ino4 binding sites in meiotic cells, evaluated chromatin structure around DSB hotspots, and measured changes in global messenger RNA levels. Our findings show that binding of these TFs has essentially no predictive power for DSB hotspot activity and definitively support the hypothesis that TF control of DSB numbers is context dependent and frequently indirect. TFs often affected the fine-scale distributions of DSBs within hotspots, and when seen, these effects paralleled effects on local chromatin structure. In contrast, changes in DSB frequencies in hotspots did not correlate with quantitative measures of chromatin accessibility, histone H3 lysine 4 trimethylation, or transcript levels. We also ruled out hotspot competition as a major source of indirect TF effects on DSB distributions. Thus, counter to prevailing models, roles of these TFs on DSB hotspot strength cannot be simply explained via chromatin "openness," histone modification, or compensatory interactions between adjacent hotspots. KEYWORDS Spo11; meiotic recombination; double-strand break; transcription factor; chromatin M EIOSIS is a specialized cell division in which one round of DNA replication is followed by two successive rounds of chromosome segregation to produce haploid gametes from diploid cells. In meiotic prophase, most sexually reproducing organisms use homologous recombination to form physical connections between homologous chromosomes that are essential for accurate chromosome segregation (Petronczki et al. 2003). Recombination also disrupts linkage of sequence polymorphisms on the same chromosome and thus promotes genome diversity and evolution (Kauppi et al. 2004).Recombination is initiated by the programmed formation of DNA double-strand breaks (DSBs). Approximately 150-200 DSBs are formed per meiosis in Saccharomyces cerevisiae (Buhler et al. 2007;Chen et al. 2008;Mancera et al. 2008;Pan et al. 2011), generated by a dimer of the topoisomerase-like protein Spo11 (Bergerat et al. 1997;Keeney et al. 1997). After break formation, Spo11 remains covalently bound to the 59 DNA strand termini (de Massy et al. 1995;Keeney and Kleckner 1995;Liu et al. 1995). Single-stranded n...

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Interaction of Genetic and Environmental Factors in Saccharomyces cerevisiae Meiosis: The Devil is in the Details

Cited by 21 publications

References 75 publications

Scale matters

Scale matters

Distinct Regulation of Mlh1p Heterodimers in Meiosis and Mitosis in Saccharomyces cerevisiae

High-Resolution Global Analysis of the Influences of Bas1 and Ino4 Transcription Factors on Meiotic DNA Break Distributions in Saccharomyces cerevisiae

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