Sharing Marks: H3K4 Methylation and H2B Ubiquitination as Features of Meiotic Recombination and Transcription

Meiosis is a specialized cell division that gives raise to four haploid gametes from a single diploid cell. During meiosis, homologous recombination is crucial to ensure genetic diversity and guarantee accurate chromosome segregation. Both the formation of programmed meiotic DNA double-strand breaks (DSBs) and their repair using homologous chromosomes are essential and highly regulated pathways. Similar to other processes that take place in the context of chromatin, histone posttranslational modifications (PTMs) constitute one of the major mechanisms to regulate meiotic recombination. In this review, we focus on specific PTMs occurring in histone tails as driving forces of different molecular events, including meiotic recombination and transcription. In particular, we concentrate on the influence of H3K4me3, H2BK123ub, and their corresponding molecular machineries that write, read, and erase these histone marks. The Spp1 subunit within the Complex of Proteins Associated with Set1 (COMPASS) is a critical regulator of H3K4me3-dependent meiotic DSB formation. On the other hand, the PAF1c (RNA polymerase II associated factor 1 complex) drives the ubiquitination of H2BK123 by Rad6-Bre1. We also discuss emerging evidence obtained by cryo-electron microscopy (EM) structure determination that has provided new insights into how the “cross-talk” between these two marks is accomplished.

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Massive crossover elevation via combination of HEI10 and recq4a recq4b during Arabidopsis meiosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713071115 ◽

2018 ◽

Vol 115 (10) ◽

pp. 2437-2442 ◽

Cited By ~ 38

Author(s):

Heïdi Serra ◽

Christophe Lambing ◽

Catherine H. Griffin ◽

Stephanie D. Topp ◽

Divyashree C. Nageswaran ◽

...

Keyword(s):

Meiotic Recombination ◽

Homologous Chromosome ◽

Crop Improvement ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Dsb Repair ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Meiotic Dsbs ◽

Competing Pathways

During meiosis, homologous chromosomes undergo reciprocal crossovers, which generate genetic diversity and underpin classical crop improvement. Meiotic recombination initiates from DNA double-strand breaks (DSBs), which are processed into single-stranded DNA that can invade a homologous chromosome. The resulting joint molecules can ultimately be resolved as crossovers. In Arabidopsis, competing pathways balance the repair of ∼100–200 meiotic DSBs into ∼10 crossovers per meiosis, with the excess DSBs repaired as noncrossovers. To bias DSB repair toward crossovers, we simultaneously increased dosage of the procrossover E3 ligase gene HEI10 and introduced mutations in the anticrossovers helicase genes RECQ4A and RECQ4B. As HEI10 and recq4a recq4b increase interfering and noninterfering crossover pathways, respectively, they combine additively to yield a massive meiotic recombination increase. Interestingly, we also show that increased HEI10 dosage increases crossover coincidence, which indicates an effect on interference. We also show that patterns of interhomolog polymorphism and heterochromatin drive recombination increases distally towards the subtelomeres in both HEI10 and recq4a recq4b backgrounds, while the centromeres remain crossover suppressed. These results provide a genetic framework for engineering meiotic recombination landscapes in plant genomes.

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CRISPR targeting of MEIOTIC-TOPOISOMERASE VIB-dCas9 to a recombination hotspot is insufficient to increase crossover frequency in Arabidopsis

10.1101/2021.02.01.429210 ◽

2021 ◽

Author(s):

Nataliya E. Yelina ◽

Sabrina Gonzalez-Jorge ◽

Dominique Hirsz ◽

Ziyi Yang ◽

Ian R. Henderson

Keyword(s):

Meiotic Recombination ◽

Crop Improvement ◽

Double Strand Breaks ◽

Crossover Frequency ◽

Dna Double Strand Breaks ◽

Crop Breeding ◽

Catalytic Subunits ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Meiotic Crossover

AbstractDuring meiosis, homologous chromosomes pair and recombine, which can result in reciprocal crossovers that increase genetic diversity. Crossovers are unevenly distributed along eukaryote chromosomes and show repression in heterochromatin and the centromeres. Within the chromosome arms crossovers are often concentrated in hotspots, which are typically in the kilobase range. The uneven distribution of crossovers along chromosomes, together with their low number per meiosis, creates a limitation during crop breeding, where recombination can be beneficial. Therefore, targeting crossovers to specific genome locations has the potential to accelerate crop improvement. In plants, meiotic crossovers are initiated by DNA double strand breaks (DSBs) that are catalysed by SPO11 complexes, which consist of two catalytic (SPO11-1 and SPO11-2) and two non-catalytic subunits (MTOPVIB). We used the model plant Arabidopsis thaliana to target a dCas9-MTOPVIB fusion protein to the 3a crossover hotspot via CRISPR. We observed that this was insufficient to significantly change meiotic crossover frequency or pattern within 3a. We discuss the implications of our findings for targeting meiotic recombination within plant genomes.

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ANKRD31 regulates spatiotemporal patterning of meiotic recombination initiation and ensures recombination between heterologous sex chromosomes in mice

10.1101/423293 ◽

2018 ◽

Cited By ~ 4

Author(s):

Frantzeskos Papanikos ◽

Julie A.J. Clément ◽

Erika Testa ◽

Ramya Ravindranathan ◽

Corinne Grey ◽

...

Keyword(s):

Sex Chromosomes ◽

Meiotic Recombination ◽

Meiotic Chromosome ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Y Chromosomes ◽

Genome Wide ◽

A Genome ◽

Pseudoautosomal Regions

AbstractOrderly segregation of chromosomes during meiosis requires that crossovers form between homologous chromosomes by recombination. Programmed DNA double-strand breaks (DSBs) initiate meiotic recombination. We identify ANKRD31 as a critical component of complexes of DSB-promoting proteins which assemble on meiotic chromosome axes. Genome-wide, ANKRD31 deficiency causes delayed recombination initiation. In addition, loss of ANKRD31 alters DSB distribution owing to reduced selectivity for sites that normally attract DSBs. Strikingly, ANKRD31 deficiency also abolishes uniquely high rates of recombination that normally characterize pseudoautosomal regions (PARs) of X and Y chromosomes. Consequently, sex chromosomes do not form crossovers leading to chromosome segregation failure in ANKRD31-deficient spermatocytes. These defects are accompanied by a genome-wide delay in assembling DSB-promoting proteins on axes and a loss of a specialized PAR-axis domain that is highly enriched for DSB-promoting proteins. Thus, we propose a model for spatiotemporal patterning of recombination by ANKRD31-dependent control of axis-associated complexes of DSB-promoting proteins.

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SPO16 binds SHOC1 to promote homologous recombination and crossing-over in meiotic prophase I

Science Advances ◽

10.1126/sciadv.aau9780 ◽

2019 ◽

Vol 5 (1) ◽

pp. eaau9780 ◽

Cited By ~ 3

Author(s):

Qianting Zhang ◽

Shu-Yan Ji ◽

Kiran Busayavalasa ◽

Chao Yu

Keyword(s):

Homologous Recombination ◽

Meiotic Recombination ◽

Double Strand Breaks ◽

Crossing Over ◽

Dna Double Strand Breaks ◽

Dsb Repair ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Recombination Nodules ◽

Evolutionarily Conserved

Segregation of homologous chromosomes in meiosis I is tightly regulated by their physical links, or crossovers (COs), generated from DNA double-strand breaks (DSBs) through meiotic homologous recombination. In budding yeast, three ZMM (Zip1/2/3/4, Mer3, Msh4/5) proteins, Zip2, Zip4, and Spo16, form a “ZZS” complex, functioning to promote meiotic recombination via a DSB repair pathway. Here, we identified the mammalian ortholog of Spo16, termed SPO16, which interacts with the mammalian ortholog of Zip2 (SHOC1/MZIP2), and whose functions are evolutionarily conserved to promote the formation of COs. SPO16 localizes to the recombination nodules, as SHOC1 and TEX11 do. SPO16 is required for stabilization of SHOC1 and proper localization of other ZMM proteins. The DSBs formed in SPO16-deleted meiocytes were repaired without COs formation, although synapsis is less affected. Therefore, formation of SPO16-SHOC1 complex–associated recombination intermediates is a key step facilitating meiotic recombination that produces COs from yeast to mammals.

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Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis

The Journal of Cell Biology ◽

10.1083/jcb.200709057 ◽

2008 ◽

Vol 180 (4) ◽

pp. 673-679 ◽

Cited By ~ 75

Author(s):

Fang Yang ◽

Sigrid Eckardt ◽

N. Adrian Leu ◽

K. John McLaughlin ◽

Peijing Jeremy Wang

Keyword(s):

Meiotic Recombination ◽

Strand Break ◽

Male Meiosis ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Recombination Proteins ◽

Meiotic Chromosomes ◽

Dna Double Strand Break

During meiosis, homologous chromosomes undergo synapsis and recombination. We identify TEX15 as a novel protein that is required for chromosomal synapsis and meiotic recombination. Loss of TEX15 function in mice causes early meiotic arrest in males but not in females. Specifically, TEX15-deficient spermatocytes exhibit a failure in chromosomal synapsis. In mutant spermatocytes, DNA double-strand breaks (DSBs) are formed, but localization of the recombination proteins RAD51 and DMC1 to meiotic chromosomes is severely impaired. Based on these data, we propose that TEX15 regulates the loading of DNA repair proteins onto sites of DSBs and, thus, its absence causes a failure in meiotic recombination.

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Massive crossover elevation via combination of HEI10 and recq4a recq4b during Arabidopsis meiosis

10.1101/159764 ◽

2017 ◽

Cited By ~ 2

Author(s):

Heïdi Serra ◽

Christophe Lambing ◽

Catherine H. Griffin ◽

Stephanie D. Topp ◽

Mathilde Séguéla-Arnaud ◽

...

Keyword(s):

Meiotic Recombination ◽

Homologous Chromosome ◽

Crop Improvement ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Dsb Repair ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Meiotic Dsbs ◽

Competing Pathways

AbstractDuring meiosis homologous chromosomes undergo reciprocal crossovers, which generate genetic diversity and underpin classical crop improvement. Meiotic recombination initiates from DNA double strand breaks, which are processed into single-stranded DNA that can invade a homologous chromosome. The resulting joint molecules can ultimately be resolved as crossovers. In Arabidopsis, competing pathways balance the repair of ∼100–200 meiotic DSBs into ∼10 crossovers per meiosis, with the excess DSBs repaired as non-crossovers. In order to bias DSB repair towards crossovers, we simultaneously increased dosage of the pro-crossover E3 ligase gene HEI10 and introduced mutations in the anti-crossover helicase genes RECQ4A and RECQ4B. As HEI10 and recq4a recq4b increase interfering and non-interfering crossover pathways respectively, they combine additively to yield a massive meiotic recombination increase. Interestingly, we also show that increased HEI10 dosage increases crossover coincidence, which indicates an effect of HEI10 on interference. We also show that patterns of interhomolog polymorphism and heterochromatin drive recombination increases towards the sub-telomeres in both HEI10 and recq4a recq4b backgrounds, while the centromeres remain crossover-suppressed. These results provide a genetic framework for engineering meiotic recombination landscapes in plant genomes.

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Phosphorylation of Histone H2B at DNA Double-Strand Breaks

Journal of Experimental Medicine ◽

10.1084/jem.20032247 ◽

2004 ◽

Vol 199 (12) ◽

pp. 1671-1677 ◽

Cited By ~ 115

Author(s):

Oscar Fernandez-Capetillo ◽

C. David Allis ◽

André Nussenzweig

Keyword(s):

Dna Damage ◽

Posttranslational Modifications ◽

Double Strand Breaks ◽

Late Time ◽

Dna Double Strand Breaks ◽

Histone Tails ◽

Histone H2b ◽

Strand Breaks ◽

Phosphorylated Form ◽

Damage Response

Posttranslational modifications of histone tails regulate numerous biological processes including transcription, DNA repair, and apoptosis. Although recent studies suggest that structural alterations in chromatin are critical for triggering the DNA damage response, very little is known about the nature of DNA damage-induced chromatin perturbations. Here we show that the serine 14 residue in the NH2-terminal tail of histone H2B is rapidly phosphorylated at sites of DNA double-strand breaks. At late time points after irradiation, the phosphorylated form of H2B, H2B-Ser14P, accumulates into irradiation-induced foci. H2B-Ser14P foci formation is not associated with the apoptotic phosphorylation of H2B but is strictly dependent on the phosphorylated isoform of H2AX. Our results broaden the spectrum of histone modifications that constitute the DNA damage “histone code” and suggest a model for the underlying chromatin structure within damage-induced foci.

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MEIOK21: a new component of meiotic recombination bridges required for spermatogenesis

Nucleic Acids Research ◽

10.1093/nar/gkaa406 ◽

2020 ◽

Vol 48 (12) ◽

pp. 6624-6639

Author(s):

Yongliang Shang ◽

Tao Huang ◽

Hongbin Liu ◽

Yanlei Liu ◽

Heng Liang ◽

...

Keyword(s):

Meiotic Recombination ◽

Double Strand Breaks ◽

Strand Exchange ◽

Homology Search ◽

Physical Interaction ◽

Dna Double Strand Breaks ◽

Dsb Repair ◽

Chromosome Localization ◽

Strand Breaks ◽

Homologous Chromosomes

Abstract Repair of DNA double-strand breaks (DSBs) with homologous chromosomes is a hallmark of meiosis that is mediated by recombination ‘bridges’ between homolog axes. This process requires cooperation of DMC1 and RAD51 to promote homology search and strand exchange. The mechanism(s) regulating DMC1/RAD51-ssDNA nucleoprotein filament and the components of ‘bridges’ remain to be investigated. Here we show that MEIOK21 is a newly identified component of meiotic recombination bridges and is required for efficient formation of DMC1/RAD51 foci. MEIOK21 dynamically localizes on chromosomes from on-axis foci to ‘hanging foci’, then to ‘bridges’, and finally to ‘fused foci’ between homolog axes. Its chromosome localization depends on DSBs. Knockout of Meiok21 decreases the numbers of HSF2BP and DMC1/RAD51 foci, disrupting DSB repair, synapsis and crossover recombination and finally causing male infertility. Therefore, MEIOK21 is a novel recombination factor and probably mediates DMC1/RAD51 recruitment to ssDNA or their stability on chromosomes through physical interaction with HSF2BP.

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Four-pronged negative feedback of DSB machinery in meiotic DNA-break control in mice

Nucleic Acids Research ◽

10.1093/nar/gkab082 ◽

2021 ◽

Author(s):

Ihsan Dereli ◽

Marcello Stanzione ◽

Fabrizio Olmeda ◽

Frantzeskos Papanikos ◽

Marek Baumann ◽

...

Keyword(s):

Negative Feedback ◽

Protein Complexes ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Damage Response ◽

Auxiliary Protein ◽

Genomic Locations ◽

Spatiotemporal Control

Abstract In most taxa, halving of chromosome numbers during meiosis requires that homologous chromosomes (homologues) pair and form crossovers. Crossovers emerge from the recombination-mediated repair of programmed DNA double-strand breaks (DSBs). DSBs are generated by SPO11, whose activity requires auxiliary protein complexes, called pre-DSB recombinosomes. To elucidate the spatiotemporal control of the DSB machinery, we focused on an essential SPO11 auxiliary protein, IHO1, which serves as the main anchor for pre-DSB recombinosomes on chromosome cores, called axes. We discovered that DSBs restrict the DSB machinery by at least four distinct pathways in mice. Firstly, by activating the DNA damage response (DDR) kinase ATM, DSBs restrict pre-DSB recombinosome numbers without affecting IHO1. Secondly, in their vicinity, DSBs trigger IHO1 depletion mainly by another DDR kinase, ATR. Thirdly, DSBs enable homologue synapsis, which promotes the depletion of IHO1 and pre-DSB recombinosomes from synapsed axes. Finally, DSBs and three DDR kinases, ATM, ATR and PRKDC, enable stage-specific depletion of IHO1 from all axes. We hypothesize that these four negative feedback pathways protect genome integrity by ensuring that DSBs form without excess, are well-distributed, and are restricted to genomic locations and prophase stages where DSBs are functional for promoting homologue pairing and crossover formation.

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End-resection at DNA double-strand breaks in the three domains of life

Biochemical Society Transactions ◽

10.1042/bst20120307 ◽

2013 ◽

Vol 41 (1) ◽

pp. 314-320 ◽

Cited By ~ 30

Author(s):

John K. Blackwood ◽

Neil J. Rzechorzek ◽

Sian M. Bray ◽

Joseph D. Maman ◽

Luca Pellegrini ◽

...

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Strand Break ◽

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Homologous Chromosomes ◽

Domains Of Life ◽

Strand Invasion ◽

End Resection

During DNA repair by HR (homologous recombination), the ends of a DNA DSB (double-strand break) must be resected to generate single-stranded tails, which are required for strand invasion and exchange with homologous chromosomes. This 5′–3′ end-resection of the DNA duplex is an essential process, conserved across all three domains of life: the bacteria, eukaryota and archaea. In the present review, we examine the numerous and redundant helicase and nuclease systems that function as the enzymatic analogues for this crucial process in the three major phylogenetic divisions.

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