Abstract
Recombination, along with sister chromatid cohesion, is used during meiosis to physically connect homologous chromosomes so that they can be segregated properly at the first meiotic division. Recombination is initiated by the introduction of programmed double strand breaks (DSBs) into the genome, a subset of which is processed into crossovers. In budding yeast, the regulation of meiotic DSB repair is controlled by a meiosis-specific kinase called Mek1. Mek1 kinase activity promotes recombination between homologs, rather than sister chromatids, as well as the processing of recombination intermediates along a pathway that results in synapsis of homologous chromosomes and the distribution of crossovers throughout the genome. In addition, Mek1 kinase activity provides a readout for the number of DSBs in the cell as part of the meiotic recombination checkpoint. This checkpoint delays entry into the first meiotic division until DSBs have been repaired by inhibiting the activity of the meiosis-specific transcription factor Ndt80, a site-specific DNA binding protein that activates transcription of over 300 target genes. Recent work has shown that Mek1 binds to Ndt80 and phosphorylates it on multiple sites, including the DNA binding domain, thereby preventing Ndt80 from activating transcription. As DSBs are repaired, Mek1 is removed from chromosomes and its activity decreases. Loss of the inhibitory Mek1 phosphates and phosphorylation of Ndt80 by the meiosis-specific kinase, Ime2, promote Ndt80 activity such that Ndt80 transcribes its own gene in a positive feedback loop, as well as genes required for the completion of recombination and entry into the meiotic divisions. Mek1 is therefore the key regulator of meiotic recombination in yeast.
Similar content being viewed by others
References
Acquaviva L, Szekvolgyi L, Dichtl B, Dichtl BS, de La Roche Saint Andre C et al. (2013) The COMPASS subunit Spp1 links histone methylation to initiation of meiotic recombination. Science 339:215–218
Adam C, Guerois R, Citarella A, Verardi L, Adolphe F et al (2018) The PHD finger protein Spp1 has distinct functions in the Set1 and the meiotic DSB formation complexes. PLoS Genet 14:e1007223
Ahmed NT, Bungard D, Shin ME, Moore M, Winter E (2009) The Ime2 protein kinase enhances the disassociation of the Sum1 repressor from middle meiotic promoters. Mol Cell Biol 29:4352–4362
Alani E, Padmore R, Kleckner N (1990) Analysis of wild-type and rad50 mutants of yeast suggests an intimate relationship between meiotic chromosome synapsis and recombination. Cell 61:419–436
Allers T, Lichten M (2001) Differential timing and control of noncrossover and crossover recombination during meiosis. Cell 106:47–57
Aravind L, Koonin EV (1998) The HORMA domain: a common structural denominator in mitotic checkpoints, chromosome synapsis and DNA repair. Trends Biochem Sci 23:284–286
Argunhan B, Leung WK, Afshar N, Terentyev Y, Subramanian VV et al (2017) Fundamental cell cycle kinases collaborate to ensure timely destruction of the synaptonemal complex during meiosis. EMBO J 36:2488–2509
Benjamin KR, Zhang C, Shokat KM, Herskowitz I (2003) Control of landmark events in meiosis by the CDK Cdc28 and the meiosis-specific kinase Ime2. Genes Dev 17:1524–1539
Bishop DK, Park D, Xu L, Kleckner N (1992) DMC1: a meiosis-specific yeast homolog of E. coli recA required for recombination, synaptonemal complex formation and cell cycle progression. Cell 69:439–456
Blat Y, Kleckner N (1999) Cohesins bind to preferential sites along yeast chromosome III, with differential regulation along arms versus the centric region. Cell 98:249–259
Brown MS, Grubb J, Zhang A, Rust MJ, Bishop DK (2015) Small Rad51 and Dmc1 complexes often co-occupy both ends of a meiotic DNA double strand break. PLoS Genet 11:e1005653
Brown SD, Jarosinska OD, Lorenz A (2018) Genetic interactions between the chromosome axis-associated protein Hop1 and homologous recombination determinants in Schizosaccharomyces pombe. Curr Genet 64:1089–1104
Busygina V, Sehorn MG, Shi IY, Tsubouchi H, Roeder GS et al (2008) Hed1 regulates Rad51-mediated recombination via a novel mechanism. Genes Dev 22:786–795
Bzymek M, Thayer NH, Oh SD, Kleckner N, Hunter N (2010) Double holliday junctions are intermediates of DNA break repair. Nature 464:937–941
Börner GV, Kleckner N, Hunter N (2004) Crossover/noncrossover differentiation, synaptonemal complex formation, and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117:29–45
Callender TL, Hollingsworth NM (2010) Mek1 suppression of meiotic double-strand break repair is specific to sister chromatids, chromosome autonomous and independent of Rec8 cohesin complexes. Genetics 185:771–782
Callender TL, Laureau R, Wan L, Chen X, Sandhu R et al (2016) Mek1 down regulates Rad51 activity during yeast meiosis by phosphorylation of Hed1. PLoS Genet 12:e1006226
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
Carlile TM, Amon A (2008) Meiosis I is established through division-specific translational control of a cyclin. Cell 133:280–291
Chen X, Gaglione R, Leong T, Bednor L, de los Santos T et al (2018) Mek1 coordinates meiotic progression with DNA break repair by directly phosphorylating and inhibiting the yeast pachytene regulator Ndt80. PloS Genet 14(11):e1007832
Chen X, Suhandynata RT, Sandhu R, Rockmill B, Mohibullah N et al (2015) Phosphorylation of the synaptonemal complex protein Zip1 regulates the crossover/noncrossover decision during yeast meiosis. PLoS Biol 13:e1002329
Chu S, Herskowitz I (1998) Gametogenesis in yeast is regulated by a transcriptional cascade dependent on Ndt80. Mol Cell 1:685–696
Cloud V, Chan Y-L, Grubb J, Budke B, Bishop DK (2012) Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis. Science 337:1222–1225
Cool M, Malone RE (1992) Molecular and genetic analysis of the yeast early meiotic recombination genes REC102 and REC107/MER2. Mol Cell Biol 12:1248–1256
Dong H, Roeder GS (2000) Organization of the yeast Zip1 protein within the central region of the synaptonemal complex. J Cell Biol 148:417–426
Goldfarb T, Lichten M (2010) Frequent and efficient use of the sister chromatid for DNA double-strand break repair during budding yeast meiosis. PLoS Biol 8:e1000520
Goldmark JP, Fazzio TG, Estep PW, Church GM, Tsukiyama T (2000) The Isw2 chromatin remodeling complex represses early meiotic genes upon recruitment by Ume6p. Cell 103:423–433
Gray S, Allison RM, Garcia V, Goldman AS, Neale MJ (2013) Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR). Open Biol 3:130019
Harrison JC, Haber JE (2006) Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet 40:209–235
Hepworth SR, Ebisuzaki LK, Segall J (1995) A 15-base-pair element activates the SPS4 gene midway through sporulation in Saccharomyces cerevisiae. Mol Cell Biol 15:3934–3944
Hollingsworth NM (2016) Mek1/Mre4 is a master regulator of meiotic recombination in budding yeast. Microbial Cell 3:129–131
Hollingsworth NM, Byers B (1989) HOP1: a yeast meiotic pairing gene. Genetics 121:445–462
Hollingsworth NM, Goetsch L, Byers B (1990) The HOP1 gene encodes a meiosis-specific component of yeast chromosomes. Cell 61:73–84
Hong S, Sung Y, Yu M, Lee M, Kleckner N et al (2013) The logic and mechanism of homologous recombination partner choice. Mol Cell 51:440–453
Hunter N (2007) Meiotic recombination. Springer, Heidelberg
Hunter N, Kleckner N (2001) The single-end invasion: an asymmetric intermediate at the double- strand break to double-holliday junction transition of meiotic recombination. Cell 106:59–70
Jin L, Zhang K, Xu Y, Sternglanz R, Neiman AM (2015) Sequestration of mRNAs modulates the timing of translation during meiosis in budding yeast. Mol Cell Biol 35:3448–3458
Joshi N, Brown MS, Bishop DK, Borner GV (2015) Gradual implementation of the meiotic recombination program via checkpoint pathways controlled by global DSB levels. Mol Cell 57:797–811
Kadyk LC, Hartwell LH (1992) Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae. Genetics 132:387–402
Kaur H, De Muyt A, Lichten M (2015) Top3-Rmi1 DNA single-strand decatenase is integral to the formation and resolution of meiotic recombination intermediates. Mol Cell 57:583–594
Keeney S, Lange J, Mohibullah N (2014) Self-organization of meiotic recombination initiation: general principles and molecular pathways. Annu Rev Genet 48:187–214
Kim KP, Weiner BM, Zhang L, Jordan A, Dekker J et al (2010) Sister cohesion and structural axis components mediate homolog bias of meiotic recombination. Cell 143:924–937
Klein F, Mahr P, Galova M, Buonomo SBC, Michaelis C et al (1999) A central role for cohesins in sister chromatid cohesion, formation of axial elements and recombination during meiosis. Cell 98:91–103
Kniewel R, Murakami H, Liu Y, Hollingsworth NM, Keeney S (2017) Histone H3 threonine 11 phosphorylation is catalyzed directly by the meiosis-specific kinase Mek1 and provides a molecular readout for Mek1 activity in vivo. Genetics 207:1313–1333
Kohl KP, Sekelsky J (2013) Meiotic and mitotic recombination in meiosis. Genetics 194:327–334
Lamoureux JS, Stuart D, Tsang R, Wu C, Glover JN (2002) Structure of the sporulation-specific transcription factor Ndt80 bound to DNA. EMBO J 21:5721–5732
Lao JP, Cloud V, Huang CC, Grubb J, Thacker D et al (2013) Meiotic crossover control by concerted action of Rad51-Dmc1 in homolog template bias and robust homeostatic regulation. PLoS Genet 9:e1003978
Lao JP, Hunter N (2010) Trying to avoid your sister. PLoS Biol 8:e1000519
Lao JP, Oh SD, Shinohara M, Shinohara A, Hunter N (2008) Rad52 promotes postinvasion steps of meiotic double-strand-break repair. Mol Cell 29:517–524
Leem S-H, Ogawa H (1992) The MRE4 gene encodes a novel protein kinase homologue required for meiotic recombination in Saccharomyces cerevisiae. Nucl Acids Res 20:449–457
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
Liu Y, Gaines WA, Callender T, Busygina V, Oke A et al (2014) Down-regulation of Rad51 activity during meiosis in yeast prevents competition with Dmc1 for repair of double-strand breaks. PLoS Genet 10:e1004005
Lo H-C, Kunz RC, Marullo A, Gygi SP, Hollingsworth NM (2012) Cdc7-Dbf4 is a gene-specific regulator of meiotic transcription in yeast. Mol Cell Bio 32:541–557
Lorenz A, Wells JL, Pryce DW, Novatchkova M, Eisenhaber F et al (2004) S. pombe meiotic linear elements contain proteins related to synaptonemal complex components. J Cell Sci 117::3343–3351
Lydall D, Nikolsky Y, Bishop DK, Weinert T (1996) A meiotic recombination checkpoint controlled by mitotic checkpoint genes. Nature 383:840–843
Lynn A, Soucek R, Borner GV (2007) ZMM proteins during meiosis: crossover artists at work. Chromosome Res 15:591–605
Mallory MJ, Cooper KF, Strich R (2007) Meiosis-specific destruction of the Ume6p repressor by the Cdc20-directed APC/C. Mol Cell 27:951–961
Malone RE, Haring SJ, Foreman KE, Pansegrau ML, Smith SM et al (2004) The signal from the initiation of meiotic recombination to the first division of meiosis. Eukaryot Cell 3:598–609
Matos J, Blanco MG, Maslen S, Skehel JM, West SC (2011) Regulatory control of the resolution of DNA recombination intermediates during meiosis and mitosis. Cell 147:158–172
McMahill MS, Sham CW, Bishop DK (2007) Synthesis-dependent strand annealing in meiosis. PLoS Biol 5:e299
Mok J, Kim PM, Lam HY, Piccirillo S, Zhou X et al (2010) Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. Sci Signal 3:ra12
Montano SP, Cote ML, Fingerman I, Pierce M, Vershon AK et al (2002) Crystal structure of the DNA-binding domain from Ndt80, a transcriptional activator required for meiosis in yeast. Proc Natl Acad Sci USA 99:14041–14046
Murakami H, Keeney S (2014) DDK links replication and recombination in meiosis. Cell Cycle 13:3621–3622
De Muyt A, Jessop L, Kolar E, Sourirajan A, Chen J et al (2012) BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism. Mol Cell 46:43–53
Niu H, Li X, Job E, Park C, Moazed D et al (2007) Mek1 kinase is regulated to suppress double-strand break repair between sister chromatids during budding yeast meiosis. Mol Cell Biol 27:5456–5467
Niu H, Wan L, Baumgartner B, Schaefer D, Loidl J et al (2005) Partner choice during meiosis is regulated by Hop1-promoted dimerization of Mek1. Mol Biol Cell 16:5804–5818
Niu H, Wan L, Busygina V, Kwon Y, Allen JA et al (2009) Regulation of meiotic recombination via Mek1-mediated Rad54 phosphorylation. Mol Cell 36:393–404
Oh SD, Lao JP, Hwang PY, Taylor AF, Smith GR et al (2007) BLM ortholog, Sgs1, prevents aberrant crossing-over by suppressing formation of multichromatid joint molecules. Cell 130:259–272
Okaz E, Arguello-Miranda O, Bogdanova A, Vinod PK, Lipp JJ et al (2012) Meiotic prophase requires proteolysis of M phase regulators mediated by the meiosis-specific APC/CAma1. Cell 151:603–618
Ozsarac N, Straffon MJ, Dalton HE, Dawes IW (1997) Regulation of gene expression during meiosis in Saccharomyces cerevisiae: SPR3 is controlled by both ABF1 and a new sporulation control element. Mol Cell Biol 17::1152–1159
Pak J, Segall J (2002) Regulation of the premiddle and middle phases of expression of the NDT80 gene during sporulation of Saccharomyces cerevisiae. Mol Cell Biol 22:6417–6429
Pan J, Sasaki M, Kniewel R, Murakami H, Blitzblau HG et al (2011) A hierarchical combination of factors shapes the genome-wide topography of yeast meiotic recombination initiation. Cell 144:719–731
Panizza S, Mendoza MA, Berlinger M, Huang L, Nicolas A et al (2011) Spo11-accessory proteins link double-strand break sites to the chromosome axis in early meiotic recombination. Cell 146:372–383
Perez-Hidalgo L, Moreno S, San-Segundo PA (2003) Regulation of meiotic progression by the meiosis-specific checkpoint kinase Mek1 in fission yeast. J Cell Sci 116::259–271
Petronczki M, Siomos MF, Nasmyth K (2003) Un menage a quatre: the molecular biology of chromosome segregation in meiosis. Cell 112:423–440
Petukhova G, Van Komen S, Vergano S, Klein H, Sung P (1999) Yeast Rad54 promotes Rad51-dependent homologous DNA pairing via ATP hydrolysis-driven change in DNA double helix conformation. J Biol Chem 274:29453–29462
Prugar E, Burnett C, Chen X, Hollingsworth NM (2017) Coordination of double strand break repair and meiotic progression in yeast by a Mek1-Ndt80 negative feedback loop. Genetics 206:497–512
Rockmill B, Engebrecht J, Scherthan H, Loidl J, Roeder GS (1995) The yeast MER2 gene is required for chromosome synapsis and the initiation of meiotic recombination. Genetics 141:49–59
Rockmill B, Roeder GS (1990) Meiosis in a synaptic yeast. Genetics 126:563–574
Rockmill B, Roeder GS (1991) A meiosis-specific protein kinase homologue required for chromosome synapsis and recombination. Genes Dev 5:2392–2404
de los Santos T, Hollingsworth NM (1999) Red1p, a MEK1-dependent phosphoprotein that physically interacts with Hop1p during meiosis in yeast. J Biol Chem 274::1783–1790
Sari F, Heinrich M, Meyer W, Braus GH, Irniger S (2008) The C-terminal region of the meiosis-specific protein kinase Ime2 mediates protein instability and is required for normal spore formation in budding yeast. J Mol Biol 378:31–43
Sasanuma H, Hirota K, Fukuda T, Kakusho N, Kugou K et al (2008) Cdc7-dependent phosphorylation of Mer2 facilitates initiation of yeast meiotic recombination. Genes Dev 22:398–410
Schwacha A, Kleckner N (1994) Identification of joint molecules that form frequently between homologs but rarely between sister chromatids. Cell 76:51–63
Schwacha A, Kleckner N (1995) Identification of double Holliday junctions as intermediates in meiotic recombination. Cell 83:783–791
Schwacha A, Kleckner N (1997) Interhomolog bias during meiotic recombination: meiotic functions promote a highly differentiated interhomolog-only pathway. Cell 90:1123–1135
Shin ME, Skokotas A, Winter E (2010) The Cdk1 and Ime2 protein kinases trigger exit from meiotic prophase in Saccharomyces cerevisiae by inhibiting the Sum1 transcriptional repressor. Mol Cell Biol 30:2996–3003
Shubassi G, Luca N, Pak J, Segall J (2003) Activity of phosphoforms and truncated versions of Ndt80, a checkpoint-regulated sporulation-specific transcription factor of Saccharomyces cerevisiae. Mol Genet Genom 270:324–336
Shuster EO, Byers B (1989) Pachytene arrest and other meiotic effects of the start mutations in Saccharomyces cerevisiae. Genetics 123:29–43
Smith AV, Roeder GS (1997) The yeast Red1 protein localizes to the cores of meiotic chromosomes. J Cell Biol 136:957–967
Sommermeyer V, Beneut C, Chaplais E, Serrentino ME, Borde V (2013) Spp1, a member of the Set1 complex, promotes meiotic DSB formation in promoters by tethering histone H3K4 methylation sites to chromosome axes. Mol Cell 49:43–54
Sopko R, Raithatha S, Stuart D (2002) Phosphorylation and maximal activity of Saccharomyces cerevisiae meiosis-specific transcription factor Ndt80 is dependent on Ime2. Mol Cell Biol 22:7024–7040
Sourirajan A, Lichten M (2008) Polo-like kinase Cdc5 drives exit from pachytene during budding yeast meiosis. Genes Dev 22:2627–2632
Strich R, Surosky RT, Steber C, Dubois E, Messenguy F et al (1994) UME6 is a key regulator of nitrogen repression and meiotic development. Genes Dev 8:796–810
Subramanian VV, Hochwagen A (2014) The meiotic checkpoint network: step-by-step through meiotic prophase. Cold Spring Harb Perspect Biol 6:a016675
Subramanian VV, MacQueen AJ, Vader G, Shinohara M, Sanchez A et al (2016) Chromosome synapsis alleviates Mek1-dependent suppression of meiotic DNA repair. PLoS Biol 14:e1002369
Suhandynata RT, Wan L, Zhou H, Hollingsworth NM (2016) Identification of putative Mek1 substrates during meiosis in Saccharomyces cerevisiae using quantitative phosphoproteomics. PLoS One 11:e0155931
Sym M, Engebrecht J, Roeder GS (1993) ZIP1 is a synaptonemal complex protein required for meiotic chromosome synapsis. Cell 72:365–378
Tang S, Wu MK, Zhang R, Hunter N (2015) Pervasive and essential roles of the Top3-Rmi1 decatenase orchestrate recombination and facilitate chromosome segregation in meiosis. Mol Cell 57:607–621
Thacker D, Mohibullah N, Zhu X, Keeney S (2014) Homologue engagement controls meiotic DNA break number and distribution. Nature 510:241–246
Tsubouchi H, Argunhan B, Tsubouchi T (2018) Exiting prophase I: no clear boundary. Curr Genet 64:423–427
Tsubouchi H, Roeder GS (2006) Budding yeast Hed1 down-regulates the mitotic recombination machinery when meiotic recombination is impaired. Genes Dev 20:1766–1775
Tung KS, Hong EJ, Roeder GS (2000) The pachytene checkpoint prevents accumulation and phosphorylation of the meiosis-specific transcription factor Ndt80. Proc Natl Acad Sci USA 97:12187–12192
Wan L, Niu H, Futcher B, Zhang C, Shokat KM et al (2008) Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast. Genes Dev 22:386–397
Wang Y, Chang CY, Wu JF, Tung KS (2011) Nuclear localization of the meiosis-specific transcription factor Ndt80 is regulated by the pachytene checkpoint. Mol Biol Cell 22:1878–1886
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 46:279–292
Winter E (2012) The Sum1/Ndt80 transcriptional switch and commitment to meiosis in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 76:1–15
Woltering D, Baumgartner B, Bagchi S, Larkin B, Loidl J 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
Wu HY, Ho HC, Burgess SM (2010) Mek1 kinase governs outcomes of meiotic recombination and the checkpoint response. Curr Biol 20:1707–1716
Xie J, Pierce M, Gailus-Durner V, Wagner M, Winter E et al (1999) Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae. EMBO J 18:6448–6454
Xu L, Ajimura M, Padmore R, Klein C, Kleckner N (1995) NDT80, a meiosis-specific gene required for exit from pachytene in Saccharomyces cerevisiae. Mol Cell Biol 15:6572–6581
Xu L, Weiner BM, Kleckner N (1997) Meiotic cells monitor the status of the interhomolog recombination complex. Genes Dev 11:106–118
Acknowledgements
The authors thank Lauren Bednor, Xiangyu Chen, Aaron Neiman and Andrew Zeisel for helpful comments on the manuscript and the members of the Hollingsworth lab for helpful discussions. This work was supported by National Institutes of Health R01 grant to N. M. H., GM050717.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by M. Kupiec.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hollingsworth, N.M., Gaglione, R. The meiotic-specific Mek1 kinase in budding yeast regulates interhomolog recombination and coordinates meiotic progression with double-strand break repair. Curr Genet 65, 631–641 (2019). https://doi.org/10.1007/s00294-019-00937-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-019-00937-3