The programmed formation of DNA double-strand breaks (DSBs) in meiotic prophase I initiates the homologous recombination process that yields crossovers between homologous chromosomes, a prerequisite to accurately segregating chromosomes during meiosis I (MI). In the budding yeast Saccharomyces cerevisiae, proteins required for meiotic DSB formation (DSB proteins) accumulate to higher levels specifically on short chromosomes to ensure that these chromosomes make DSBs. We previously demonstrated that as-yet undefined cis-acting elements preferentially recruit DSB proteins and promote higher levels of DSBs and recombination and that these intrinsic features are subject to selection pressure to maintain the hyperrecombinogenic properties of short chromosomes. Thus, this targeted boosting of DSB protein binding may be an evolutionarily recurrent strategy to mitigate the risk of meiotic mis-segregation caused by karyotypic constraints. However, the underlining mechanisms are still elusive. Here, we discuss possible scenarios in which components of the meiotic chromosome axis (Red1 and Hop1) bind to intrinsic features independent of the meiosis-specific cohesin subunit Rec8 and DNA replication, promoting preferential binding of DSB proteins to short chromosomes. We also propose a model where chromosome position in the nucleus, influenced by centromeres, promotes the short-chromosome boost of DSB proteins.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Acquaviva L, Boekhout M, Karasu ME et al (2020) Ensuring meiotic DNA break formation in the mouse pseudoautosomal region. Nature. https://doi.org/10.1038/s41586-020-2327-4
Arora C, Kee K, Maleki S, Keeney S (2004) Antiviral protein Ski8 is a direct partner of Spo11 in meiotic DNA break formation, independent of its cytoplasmic role in RNA metabolism. Mol Cell 13:549–559. https://doi.org/10.1016/s1097-2765(04)00063-2
Blat Y, Protacio RU, Hunter N, Kleckner N (2002) Physical and functional interactions among basic chromosome organizational features govern early steps of meiotic chiasma formation. Cell 111:791–802. https://doi.org/10.1016/s0092-8674(02)01167-4
Blitzblau HG, Chan CS, Hochwagen A, Bell SP (2012) Separation of DNA replication from the assembly of break-competent meiotic chromosomes. PLoS Genet 8:e1002643. https://doi.org/10.1371/journal.pgen.1002643PGENETICS-D-11-02760[pii]
Börner GV, Barot A, Kleckner N (2008) Yeast Pch2 promotes domainal axis organization, timely recombination progression, and arrest of defective recombinosomes during meiosis. Proc Natl Acad Sci USA 105:3327–3332. https://doi.org/10.1073/pnas.0711864105
Burgess SM, Kleckner N (1999) Collisions between yeast chromosomal loci in vivo are governed by three layers of organization. Genes Dev. https://doi.org/10.1101/gad.13.14.1871
Carballo JA, Johnson AL, Sedgwick SG, Cha RS (2008) Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination. Cell 132:758–770. https://doi.org/10.1016/j.cell.2008.01.035
Chen SY, Tsubouchi T, Rockmill B et al (2008) Global analysis of the meiotic crossover landscape. Dev Cell 15:401–415. https://doi.org/10.1016/j.devcel.2008.07.006
Chen C, Jomaa A, Ortega J, Alani EE (2014) Pch2 is a hexameric ring ATPase that remodels the chromosome axis protein Hop1. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1310755111
Claeys Bouuaert C, Pu S, Wang J, Oger C, Daccache D, Xie W, Patel DJ, and Keeney S (2021) DNA-driven condensation assembles the meiotic DNA break machinery. Nature. https://doi.org/10.1101/2020.02.21.960245
Heldrich J, Markowitz TE, Vale-Silva LA, Hochwagen A (2020) A cohesin-independent mechanism modulates recombination activity along meiotic chromosomes. bioRxiv. https://doi.org/10.1101/2020.08.11.247122
Henderson KA, Kee K, Maleki S et al (2006) Cyclin-dependent kinase directly regulates initiation of meiotic recombination. Cell 125:1321–1332. https://doi.org/10.1016/j.cell.2006.04.039
Hollingsworth NM, Goetsch L, Byers B (1990) The HOP1 gene encodes a meiosis-specific component of yeast chromosomes. Cell. https://doi.org/10.1016/0092-8674(90)90216-2
Hunter N (2015) Meiotic recombination: the essence of heredity. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a016618
Jin QW, Trelles-Sticken E, Scherthan H, Loidl J (1998) Yeast nuclei display prominent centromere clustering that is reduced in nondividing cells and in meiotic prophase. J Cell Biol. https://doi.org/10.1083/jcb.141.1.21
Jin QW, Fuchs J, Loidl J (2000) Centromere clustering is a major determinant of yeast interphase nuclear organization. J Cell Sci 113:1903–1912
Kaback DB, Guacci V, Barber D, Mahon JW (1992) Chromosome size-dependent control of meiotic recombination. Science 256:228–232
Kariyazono R, Oda A, Yamada T, Ohta K (2019) Conserved HORMA domain-containing protein Hop1 stabilizes interaction between proteins of meiotic DNA break hotspots and chromosome axis. Nucleic Acids Res. https://doi.org/10.1093/nar/gkz754
Kironmai KM, Muniyappa K, Friedman DB et al (1998) DNA-binding activities of Hop1 protein, a synaptonemal complex component from Saccharomyces cerevisiae. Mol Cell Biol. https://doi.org/10.1128/mcb.18.3.1424
Klein F, Mahr P, Galova M et al (1999) A central role for cohesins in sister chromatid cohesion, formation of axial elements, and recombination during yeast meiosis. Cell 98:91–103. https://doi.org/10.1016/S0092-8674(00)80609-1
Kshirsagar R, Ghodke I, Muniyappa K (2017) Saccharomyces cerevisiae Red1 protein exhibits nonhomologous DNA end–joining activity and potentiates Hop1-promoted pairing of double-stranded DNA. J Biol Chem. https://doi.org/10.1074/jbc.M117.796425
Kugou K, Fukuda T, Yamada S et al (2009) Rec8 guides canonical Spo11 distribution along yeast meiotic chromosomes. Mol Biol Cell 20:3064–3076. https://doi.org/10.1091/mbc.E08-12-1223
Lam I, Keeney S (2015) Mechanism and regulation of meiotic recombination initiation. Cold Spring Harbor Perspect Biol. https://doi.org/10.1101/cshperspect.a016634
Lazar-Stefanita L, Scolari VF, Mercy G et al (2017) Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cell cycle. EMBO J. https://doi.org/10.15252/embj.201797342
Lengronne A, Katou Y, Mori S et al (2004) Cohesin relocation from sites of chromosomal loading to places of convergent transcription. Nature 430:573–578. https://doi.org/10.1038/nature02742
Li J, Hooker GW, Roeder GS (2006) Saccharomyces cerevisiae Mer2, Mei4 and Rec114 form a complex required for meiotic double-strand break formation. Genetics 173:1969–1981. https://doi.org/10.1534/genetics.106.058768
Luo J, Mercy G, Vale-Silva LA et al (2018) Synthetic chromosome fusion: effects on genome structure and function. bioRxiv. https://doi.org/10.1101/381137
Maleki S, Neale MJ, Arora C et al (2007) Interactions between Mei4, Rec114, and other proteins required for meiotic DNA double-strand break formation in Saccharomyces cerevisiae. Chromosoma 116:471–486. https://doi.org/10.1007/s00412-007-0111-y
Mancera E, Bourgon R, Brozzi A et al (2008) High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Nature 454:479–485. https://doi.org/10.1038/nature07135
Mao-Draayer Y, Galbraith AM, Pittman DL et al (1996) Analysis of meiotic recombination pathways in the yeast Saccharomyces cerevisiae. Genetics 144:71–86
Markowitz TE, Suarez D, Blitzblau HG et al (2017) Reduced dosage of the chromosome axis factor Red1 selectively disrupts the meiotic recombination checkpoint in Saccharomyces cerevisiae. PLoS Genet 13:e1006928. https://doi.org/10.1371/journal.pgen.1006928
Muller H, Scolari VF, Agier N et al (2018) Characterizing meiotic chromosomes’ structure and pairing using a designer sequence optimized for Hi-C. Mol Syst Biol. https://doi.org/10.15252/msb.20188293
Muniyappa K, Anuradha S, Byers B (2000) Yeast meiosis-specific protein hop1 binds to G4 DNA and promotes its formation. Mol Cell Biol. https://doi.org/10.1128/mcb.20.4.1361-1369.2000
Murakami H, Keeney S (2014) Temporospatial coordination of meiotic DNA replication and recombination via DDK recruitment to replisomes. Cell 158:861–873. https://doi.org/10.1016/j.cell.2014.06.028
Murakami H, Lam I, Huang P-C et al (2020) Multilayered mechanisms ensure that short chromosomes recombine in meiosis. Nature 582:124–128. https://doi.org/10.1038/s41586-020-2248-2
Niu H, Wan L, Baumgartner B et al (2005) Partner choice during meiosis is regulated by Hop1-promoted dimerization of Mek1. Mol Biol Cell 16:5804–5818. https://doi.org/10.1091/mbc.e05-05-0465
Pan J, Sasaki M, Kniewel R et al (2011) A hierarchical combination of factors shapes the genome-wide topography of yeast meiotic recombination initiation. Cell 144:719–731. https://doi.org/10.1016/j.cell.2011.02.009
Panizza S, Mendoza MA, Berlinger M et al (2011) Spo11-accessory proteins link double-strand break sites to the chromosome axis in early meiotic recombination. Cell 146:372–383. https://doi.org/10.1016/j.cell.2011.07.003
Raina VB, Vader G (2020) Homeostatic control of meiotic prophase checkpoint function by Pch2 and Hop1. Curr Biol 30:4413-4424.e5. https://doi.org/10.1016/j.cub.2020.08.064
Rosenberg SC, Corbett KD (2015) The multifaceted roles of the HOR MA domain in cellular signaling. J Cell Biol 211:745–755
Rousova D, Funk SK, Reichle H, Weir JR (2020) Mer2 binds directly to both nucleosomes and axial proteins as the keystone of meiotic recombination. bioRxiv 46:29
Rüthnick D, Neuner A, Dietrich F et al (2017) Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes. J Cell Biol. https://doi.org/10.1083/jcb.201612129
Schalbetter SA, Fudenberg G, Baxter J et al (2019) Principles of meiotic chromosome assembly revealed in S. cerevisiae. Nat Commun. https://doi.org/10.1038/s41467-019-12629-0
Smith AV, Roeder GS (1997) The yeast Red1 protein localizes to the cores of meiotic chromosomes. J Cell Biol. https://doi.org/10.1083/jcb.136.5.957
Subramanian VV, MacQueen AJ, Vader G et al (2016) Chromosome synapsis alleviates Mek1-dependent suppression of meiotic DNA repair. PLoS Biol 14:e1002369. https://doi.org/10.1371/journal.pbio.1002369
Subramanian VV, Zhu X, Markowitz TE et al (2019) Persistent DNA-break potential near telomeres increases initiation of meiotic recombination on short chromosomes. Nat Commun 10:970. https://doi.org/10.1038/s41467-019-08875-x
Sun X, Huang L, Markowitz TE et al (2015) Transcription dynamically patterns the meiotic chromosome-axis interface. eLife. https://doi.org/10.7554/eLife.07424
Vale-Silva LA, Markowitz TE, Hochwagen A (2019) SNP-ChIP: a versatile and tag-free method to quantify changes in protein binding across the genome. BMC Genom. https://doi.org/10.1186/s12864-018-5368-4
West AMV, Komives EA, Corbett KD (2018) Conformational dynamics of the Hop1 HORMA domain reveal a common mechanism with the spindle checkpoint protein Mad2. Nucleic Acids Res. https://doi.org/10.1093/nar/gkx1196
West AM, Rosenberg SC, Ur SN et al (2019) A conserved filamentous assembly underlies the structure of the meiotic chromosome axis. eLife. https://doi.org/10.7554/eLife.40372
Wojtasz L, Daniel K, Roig I et al (2009) Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet 5:e1000702. https://doi.org/10.1371/journal.pgen.1000702
Woltering D, Baumgartner B, Bagchi S et al (2000) Meiotic segregation, synapsis, and recombination checkpoint functions require physical interaction between the chromosomal proteins Red1p and Hop1p. Mol Cell Biol 20:6646–6658
Yue JX, Li J, Aigrain L et al (2017) Contrasting evolutionary genome dynamics between domesticated and wild yeasts. Nat Genet 49:913–924. https://doi.org/10.1038/ng.3847
This work was supported by NIH grant R35 GM118092 to SK. MSKCC core facilities are supported by NCI Cancer Center Support Grant P30 CA008748.
Conflict of interest
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Communicated by Michael Polymenis.
About this article
Cite this article
Murakami, H., Mu, X. & Keeney, S. How do small chromosomes know they are small? Maximizing meiotic break formation on the shortest yeast chromosomes. Curr Genet (2021). https://doi.org/10.1007/s00294-021-01160-9
- DNA double-strand breaks
- Chromosome segregation
- Chromosome evolution
- Chromosome structure