Histone methylation sets the stage for meiotic DNA breaks

Kniewel, R.; Keeney, Scott

doi:10.1038/emboj.2008.277

Cited by 20 publications

(18 citation statements)

References 15 publications

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“…Because PRDM9 is essential for generation of DSBs in meiotic recombination, H3K4me3 is assumed to indirectly recruit Spo11 (Top2). In yeast meiotic recombination, H3K4me3 mark and consequent DSB are dependent on Set1 histone methyltransferase, which is regulated by Bre1, as we showed for CSR (28,33). Thus, both CSR and meiotic recombination appear to require transcription of the weakly conserved target DNA and the H3K4me3 mark for recruiting the cleavaging enzyme (Table S2).…”

Section: Discussionmentioning

confidence: 74%

Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination

Stanlie

Aida

Muramatsu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

100

141

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Ig class switch recombination (CSR) requires expression of activation-induced cytidine deaminase (AID) and transcription through target switch (S) regions. Here we show that knockdown of the histone chaperone facilitates chromatin transcription (FACT) completely inhibited S region cleavage and CSR in IgA-switch-inducible CH12F3-2A B cells. FACT knockdown did not reduce AID or S region transcripts but did decrease histone3 lysine4 trimethylation (H3K4me3) at both the Sμ and Sα regions. Because knockdown of FACT or H3K4 methyltransferase cofactors inhibited DNA cleavage in H3K4me3-depleted S regions, H3K4me3 may serve as a mark for recruiting CSR recombinase. These findings revealed an unexpected evolutionary conservation between CSR and meiotic recombination.A ntigen stimulation of B lymphocytes induces the expression of activation-induced cytidine deaminase (AID), which is responsible for generation of antibody memory (1, 2). Somatic hypermutation and class switch recombination (CSR) are two genetic events that engrave antibody memory into the Ig heavychain (H) locus of the B cell genome. CSR takes place between two switch (S) regions, located upstream of the individual H constant regions (C H ) and converts the isotype from IgM to another class by bringing the specific C H region close to the H variable region (V H ) exons and looping out the intervening DNA segment (3).Gene-targeting experiments in the IgH locus have shown that active transcription through the S regions is an essential requirement of CSR (4, 5). This transcription initiates from the I promoter, located upstream of each S region, and proceeds through the I exon, the intronic S region, the C H exons, and the C H introns. The mature transcripts, designated as germline transcripts (GLTs), are generated by splicing out the S region and C H intronic sequences (3). However, it is not well understood whether the transcription itself, the transcription products, or both are important for CSR. The original chromatin-opening hypothesis suggested that transcription of the S region causes its chromatin structure to be relatively open, which increases its accessibility to a putative recombinase (6, 7). In fact, the migration of the transcription machinery accumulates positive and negative supercoil in its front and rear, respectively.During this process, R-loop formation was detected in the DNA from switching B cells by the bisulfite sensitivity assay (8). The R-loop formation was considered to support the DNA deamination hypothesis proposed for the function of AID, as the single-strand DNA can serve as an efficient substrate of cytidine deamination by AID, as demonstrated in vitro (9). This hypothesis postulates that dU generated by AID deamination is recognized as a dU/dG mismatch and excised by uracil DNA glycosylase (10). The abasic sites thus formed is then cleaved by apyrimidinic/apurinic endonuclease. It has been also proposed that dU/dG mismatches are recognized and cleaved by mismatch repair proteins such as Msh2 and Msh6.On the other hand, AID was...

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Section: Discussionmentioning

confidence: 74%

Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination

Stanlie

Aida

Muramatsu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

100

141

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“…10,[15][16][17][18][19][20] One feature that has received considerable attention as a potential determinant of DSB location in yeast is the posttranslational trimethylation of lysine 4 of histone H3 (H3K4me3). [21][22][23][24][25] The Set1 lysine methyltransferase is responsible for all mono-, di-and trimethylation of H3K4 in S. cerevisiae, 26,27 and set1 mutants display altered DSB distributions. 21,23 Moreover, a strong spatial correlation has been observed, in which regions with high DSB levels also display significant H3K4me3 enrichment, [21][22][23][24][25] leading to the hypothesis that H3K4me3 is a "prominent and preexisting mark" of meiotic recombination sites, independent of transcript level of nearby genes.…”

Section: The Importance Of Scalementioning

confidence: 99%

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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“…However, it is not known how these signals integrate with factors that control the association of chromatin with the chromosome axis. Furthermore, the H3K4Me3 mark is highly enriched in promoter regions of actively transcribed genes (Bernstein et al, 2005;Schneider et al, 2004), but meiotic DSBs do not form in all promoter regions and, currently, there is no known direct relationship between DSB formation and transcriptional activity (Hunter, 2006;Kniewel and Keeney, 2009). Thus, this chromatin modification alone is not likely to account for all hotspot activity.…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

The choice in meiosis – defining the factors that influence crossover or non-crossover formation

Youds

Boulton

2011

Journal of Cell Science

149

130

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Commentary 501 IntroductionMeiosis is the specialised reductive division that generates haploid cells. During this process, a single round of replication is followed by two rounds of chromosome segregation: in the first division (meiosis I), homologous chromosomes segregate, whereas in the second division, sister chromatids segregate (meiosis II). A key step in meiosis I is the recognition of homologous chromosomes, which then align and pair along the length of the chromosome. Once homologues have aligned, synapsis can proceed with the formation of the synaptonemal complex (SC), a protein structure that supports and maintains homologues in close juxtaposition and serves as a scaffold for crossover-promoting recombination factors. Meiotic crossing over involves the generation of meiotic doublestrand breaks (DSBs), which are subsequently repaired either as crossovers or non-crossovers (Fig. 1). Meiotic recombination is not only necessary to create new allele combinations that generate genetic diversity, but is also essential in ensuring accurate chromosome segregation at the first meiotic division because the crossover acts as a tether between homologues, which ensures that each homologue will properly align at the metaphase plate and thereby correctly attach to the spindle. DSB repair occurs concurrently with SC formation and is required for normal synapsis in yeast and mice (Baudat et al., 2000;Roeder, 1997;Romanienko and Camerini-Otero, 2000), whereas in Caenorhabditis elegans and Drosophila melanogaster, homologue pairing and SC formation can occur independently of meiotic recombination (Colaiacovo et al., 2003; Dernburg et al., 1998;Liu et al., 2002;McKim et al., 1998).The process of meiotic recombination is initiated when meiotic DSBs are created by the endonuclease SPO11, in conjunction with a number of additional proteins (Keeney and Neale, 2006). DSBs are then resected to generate 3Ј single-strand DNA (ssDNA) overhangs that are initially bound by replication protein A (RPA), which is subsequently displaced by the recombinase radiation sensitive 51 (RAD51) and/or the meiosis-specific recombinase dosage suppressor of Mck1 (DMC1) to form nucleoprotein filaments. These filaments serve to find a complimentary sequence within a homologous chromosome, at which they instigate singleend strand invasions (Hunter and Kleckner, 2001) to generate socalled displacement loop (D loop) recombination intermediates ( Fig. 1). If the second end of the original DSB binds with the homologous chromosome, a double Holliday junction is formed, which can be resolved to generate either a non-crossover or an interhomologue crossover, the latter of which is hereafter referred to simply as crossover (Bishop and Zickler, 2004;Schwacha and Kleckner, 1995). Double Holliday junctions can also be processed through dissolution, which results in a non-crossover ( Fig. 1) (Wu and Hickson, 2003). Meiotic non-crossovers have also been proposed to form when strand invasion is transient, and when a limited amount of DNA synthesis occurs befor...

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Histone methylation sets the stage for meiotic DNA breaks

Cited by 20 publications

References 15 publications

Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination

Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination

Scale matters

The choice in meiosis – defining the factors that influence crossover or non-crossover formation

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