Faithful chromosome segregation during meiosis requires that homologous chromosomes associate and recombine. Chiasmata, the cytological manifestation of recombination, provide the physical link that holds the homologs together as a pair, facilitating their orientation on the spindle at meiosis I. Formation of most crossover (CO) events requires the assistance of a group of proteins collectively known as ZMM. HFM1/Mer3 is in this group of proteins and is required for normal progression of homologous recombination and proper synapsis between homologous chromosomes in a number of model organisms. Our work is the first study in mammals showing the in vivo function of mouse HFM1. Cytological observations suggest that initial steps of recombination are largely normal in a majority of Hfm1−/− spermatocytes. Intermediate and late stages of recombination appear aberrant, as chromosomal localization of MSH4 is altered and formation of MLH1foci is drastically reduced. In agreement, chiasma formation is reduced, and cells arrest with subsequent apoptosis at diakinesis. Our results indicate that deletion of Hfm1 leads to the elimination of a major fraction but not all COs. Formation of chromosome axial elements and homologous pairing is apparently normal, and Hfm1−/− spermatocytes progress to the end of prophase I without apparent developmental delay or apoptosis. However, synapsis is altered with components of the central region of the synaptonemal complex frequently failing to extend the full length of the chromosome axes. We propose that initial steps of recombination are sufficient to support homology recognition, pairing, and initial chromosome synapsis and that HFM1 is required to form normal numbers of COs and to complete synapsis.
Vyšlo v časopise: Mouse HFM1/Mer3 Is Required for Crossover Formation and Complete Synapsis of Homologous Chromosomes during Meiosis. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003383 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003383
1. KlecknerN (1996) Meiosis: how could it work? Proc Natl Acad Sci U S A 93 : 8167–8174.
2. RoederGS (1997) Meiotic chromosomes: it takes two to tango. Genes Dev 11 : 2600–2621.
3. EdelmannW, CohenPE, KaneM, LauK, MorrowB, et al. (1996) Meiotic pachytene arrest in MLH1-deficient mice. Cell 85 : 1125–1134.
4. HassoldT, HuntP (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2 : 280–291.
5. HassoldTJ, JacobsPA (1984) Trisomy in man. Annu Rev Genet 18 : 69–97.
6. RomanienkoPJ, Camerini-OteroRD (2000) The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 6 : 975–987.
7. KeeneyS, GirouxCN, KlecknerN (1997) Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88 : 375–384.
8. KeeneyS, BaudatF, AngelesM, ZhouZH, CopelandNG, et al. (1999) A mouse homolog of the Saccharomyces cerevisiae meiotic recombination DNA transesterase Spo11p. Genomics 61 : 170–182.
9. PâquesF, HaberJE (1999) Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews 63 : 349–404.
10. MimitouEP, SymingtonLS (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455 : 770–774.
11. ZhuZ, ChungWH, ShimEY, LeeSE, IraG (2008) Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134 : 981–994.
12. GravelS, ChapmanJR, MagillC, JacksonSP (2008) DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev 22 : 2767–2772.
13. PezzaRJ, VoloshinON, VanevskiF, Camerini-OteroRD (2007) Hop2/Mnd1 acts on two critical steps in Dmc1-promoted homologous pairing. Genes & Development 21 : 1758–1766.
14. ChiP, San FilippoJ, SehornMG, PetukhovaGV, SungP (2007) Bipartite stimulatory action of the Hop2-Mnd1 complex on the Rad51 recombinase. Genes Dev 21 : 1747–1757.
15. NealeMJ, KeeneyS (2006) Clarifying the mechanics of DNA strand exchange in meiotic recombination. Nature 442 : 153–158.
16. BiancoPR, TracyRB, KowalczykowskiSC (1998) DNA strand exchange proteins: a biochemical and physical comparison. Front Biosci 3: D570–603.
17. SungP, KrejciL, Van KomenS, SehornMG (2003) Rad51 recombinase and recombination mediators. J Biol Chem 278 : 42729–42732.
18. AllersT, LichtenM (2001) Differential timing and control of noncrossover and crossover recombination during meiosis. Cell 106 : 47–57.
19. NassifN, PenneyJ, PalS, EngelsWR, GloorGB (1994) Efficient copying of nonhomologous sequences from ectopic sites via P-element-induced gap repair. Molecular and cellular biology 14 : 1613–1625.
20. HunterN, KlecknerN (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.
21. BornerGV, KlecknerN, HunterN (2004) Crossover/noncrossover differentiation, synaptonemal complex formation, and regulatory surveillance at the leptotene/zygotene transition of meiosis. Cell 117 : 29–45.
22. BishopDK, ZicklerD (2004) Early decision; meiotic crossover interference prior to stable strand exchange and synapsis. Cell 117 : 9–15.
23. SchwachaA, KlecknerN (1995) Identification of double Holliday junctions as intermediates in meiotic recombination. Cell 83 : 783–791.
24. JessopL, RockmillB, RoederGS, LichtenM (2006) Meiotic chromosome synapsis-promoting proteins antagonize the anti-crossover activity of sgs1. PLoS Genet 2: e155 doi:10.1371/journal.pgen.0020155
25. SzostakJW, Orr-WeaverTL, RothsteinRJ, StahlFW (1983) The double-strand break repair model for recombination. Cell 33 : 25–35.
26. HollowayJK, BoothJ, EdelmannW, McGowanCH, CohenPE (2008) MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLoS Genet 4: e1000186 doi:10.1371/journal.pgen.1000186
27. LynnA, SoucekR, BornerGV (2007) ZMM proteins during meiosis: crossover artists at work. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 15 : 591–605.
28. MercierR, JolivetS, VezonD, HuppeE, ChelyshevaL, et al. (2005) Two meiotic crossover classes cohabit in Arabidopsis: one is dependent on MER3,whereas the other one is not. Current biology : CB 15 : 692–701.
29. GuillonH, BaudatF, GreyC, LiskayRM, de MassyB (2005) Crossover and noncrossover pathways in mouse meiosis. Molecular Cell 20 : 563–573.
30. BerchowitzLE, FrancisKE, BeyAL, CopenhaverGP (2007) The role of AtMUS81 in interference-insensitive crossovers in A. thaliana. PLoS Genet 3: e132 doi:10.1371/journal.pgen.0030132
31. HigginsJD, BucklingEF, FranklinFC, JonesGH (2008) Expression and functional analysis of AtMUS81 in Arabidopsis meiosis reveals a role in the second pathway of crossing-over. The Plant journal : for cell and molecular biology 54 : 152–162.
32. CopenhaverGP (2005) Plant genetics: when not to interfere. Current biology : CB 15: R290–291.
33. SymM, EngebrechtJA, RoederGS (1993) ZIP1 is a synaptonemal complex protein required for meiotic chromosome synapsis. Cell 72 : 365–378.
34. de VriesFA, de BoerE, van den BoschM, BaarendsWM, OomsM, et al. (2005) Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev 19 : 1376–1389.
35. HigginsJD, Sanchez-MoranE, ArmstrongSJ, JonesGH, FranklinFC (2005) The Arabidopsis synaptonemal complex protein ZYP1 is required for chromosome synapsis and normal fidelity of crossing over. Genes & Development 19 : 2488–2500.
36. ColaiacovoMP, MacQueenAJ, Martinez-PerezE, McDonaldK, AdamoA, et al. (2003) Synaptonemal complex assembly in C. elegans is dispensable for loading strand-exchange proteins but critical for proper completion of recombination. Developmental cell 5 : 463–474.
37. PageSL, HawleyRS (2004) The genetics and molecular biology of the synaptonemal complex. Annu Rev Cell Dev Biol 20 : 525–558.
38. ChenC, ZhangW, TimofejevaL, GerardinY, MaH (2005) The Arabidopsis ROCK-N-ROLLERS gene encodes a homolog of the yeast ATP-dependent DNA helicase MER3 and is required for normal meiotic crossover formation. The Plant journal : for cell and molecular biology 43 : 321–334.
39. SugawaraH, IwabataK, KoshiyamaA, YanaiT, DaikuharaY, et al. (2009) Coprinus cinereus Mer3 is required for synaptonemal complex formation during meiosis. Chromosoma 118 : 127–139.
40. TanakaK, MiyamotoN, Shouguchi-MiyataJ, IkedaJE (2006) HFM1, the human homologue of yeast Mer3, encodes a putative DNA helicase expressed specifically in germ-line cells. DNA sequence : the journal of DNA sequencing and mapping 17 : 242–246.
41. ZalevskyJ, MacQueenAJ, DuffyJB, KemphuesKJ, VilleneuveAM (1999) Crossing over during Caenorhabditis elegans meiosis requires a conserved MutS-based pathway that is partially dispensable in budding yeast. Genetics 153 : 1271–1283.
42. KellyKO, DernburgAF, StanfieldGM, VilleneuveAM (2000) Caenorhabditis elegans msh-5 is required for both normal and radiation-induced meiotic crossing over but not for completion of meiosis. Genetics 156 : 617–630.
43. KneitzB, CohenPE, AvdievichE, ZhuL, KaneMF, et al. (2000) MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev 14 : 1085–1097.
44. HigginsJD, ArmstrongSJ, FranklinFC, JonesGH (2004) The Arabidopsis MutS homolog AtMSH4 functions at an early step in recombination: evidence for two classes of recombination in Arabidopsis. Genes & Development 18 : 2557–2570.
45. Martinez-PerezE, ColaiacovoMP (2009) Distribution of meiotic recombination events: talking to your neighbors. Current opinion in genetics & development 19 : 105–112.
46. HillersKJ (2004) Crossover interference. Current biology : CB 14: R1036–1037.
47. KlecknerN, ZicklerD, JonesGH, DekkerJ, PadmoreR, et al. (2004) A mechanical basis for chromosome function. Proceedings of the National Academy of Sciences of the United States of America 101 : 12592–12597.
48. de los SantosT, HunterN, LeeC, LarkinB, LoidlJ, et al. (2003) The Mus81/Mms4 endonuclease acts independently of double-Holliday junction resolution to promote a distinct subset of crossovers during meiosis in budding yeast. Genetics 164 : 81–94.
49. CopenhaverGP, HousworthEA, StahlFW (2002) Crossover interference in Arabidopsis. Genetics 160 : 1631–1639.
50. NakagawaT, KolodnerRD (2002) Saccharomyces cerevisiae Mer3 Is a DNA Helicase Involved in Meiotic Crossing Over. Mol Cell Biol 22 : 3281–3291.
51. MazinaOM, MazinAV, NakagawaT, KolodnerRD, KowalczykowskiSC (2004) Saccharomyces cerevisiae Mer3 helicase stimulates 3′-5′ heteroduplex extension by Rad51; implications for crossover control in meiotic recombination. Cell 117 : 47–56.
52. NakagawaT, OgawaH (1999) The Saccharomyces cerevisiae MER3 gene, encoding a novel helicase-like protein, is required for crossover control in meiosis. EMBO J 18 : 5714–5723.
53. WangK, TangD, WangM, LuJ, YuH, et al. (2009) MER3 is required for normal meiotic crossover formation, but not for presynaptic alignment in rice. Journal of cell science 122 : 2055–2063.
54. StorlazziA, GarganoS, Ruprich-RobertG, FalqueM, DavidM, et al. (2010) Recombination proteins mediate meiotic spatial chromosome organization and pairing. Cell 141 : 94–106.
55. PetukhovaGV, RomanienkoPJ, Camerini-OteroRD (2003) The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis. Dev Cell 5 : 927–936.
56. PittmanDL, CobbJ, SchimentiKJ, WilsonLA, CooperDM, et al. (1998) Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol Cell 1 : 697–705.
57. HunterN, Valentin BornerG, LichtenM, KlecknerN (2001) Gamma-H2AX illuminates meiosis. Nat Genet 27 : 236–238.
58. BannisterLA, PezzaRJ, DonaldsonJR, de RooijDG, SchimentiKJ, et al. (2007) A dominant, recombination-defective allele of Dmc1 causing male-specific sterility. PLoS Biol 5: e105 doi:10.1371/journal.pbio.0050105
59. MahadevaiahSK, TurnerJM, BaudatF, RogakouEP, de BoerP, et al. (2001) Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet 27 : 271–276.
60. DresserM, PisetskyD, WarrenR, McCartyG, MosesM (1987) A new method for the cytological analysis of autoantibody specificities using whole-mount, surface-spread meiotic nuclei. J Immunol Methods 104 : 111–121.
61. AshleyT, PlugAW, XuJ, SolariAJ, ReddyG, et al. (1995) Dynamic changes in Rad51 distribution on chromatin during meiosis in male and female vertebrates. Chromosoma 104 : 19–28.
62. MoensPB, ChenDJ, ShenZ, KolasN, TarsounasM, et al. (1997) Rad51 immunocytology in rat and mouse spermatocytes and oocytes. Chromosoma 106 : 207–215.
63. AndersonLK, ReevesA, WebbLM, AshleyT (1999) Distribution of crossing over on mouse synaptonemal complexes using immunofluorescent localization of MLH1 protein. Genetics 151 : 1569–1579.
64. de BoerE, StamP, DietrichAJ, PastinkA, HeytingC (2006) Two levels of interference in mouse meiotic recombination. Proc Natl Acad Sci U S A 103 : 9607–9612.
65. RoigI, DowdleJA, TothA, de RooijDG, JasinM, et al. (2010) Mouse TRIP13/PCH2 is required for recombination and normal higher-order chromosome structure during meiosis. PLoS Genet 6: e1001062 doi:10.1371/journal.pgen.1001062
66. PetronczkiM, SiomosMF, NasmythK (2003) Un menage a quatre: the molecular biology of chromosome segregation in meiosis. Cell 112 : 423–440.
67. TerasawaM, OgawaH, TsukamotoY, ShinoharaM, ShirahigeK, et al. (2007) Meiotic recombination-related DNA synthesis and its implications for cross-over and non-cross-over recombinant formation. Proceedings of the National Academy of Sciences of the United States of America 104 : 5965–5970.
68. RockmillB, FungJC, BrandaSS, RoederGS (2003) The Sgs1 helicase regulates chromosome synapsis and meiotic crossing over. Curr Biol 13 : 1954–1962.
69. LipkinSM, MoensPB, WangV, LenziM, ShanmugarajahD, et al. (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nature Genetics 31 : 385–390.
70. GhabrialA, SchupbachT (1999) Activation of a meiotic checkpoint regulates translation of Gurken during Drosophila oogenesis. Nature cell biology 1 : 354–357.
71. BhallaN, DernburgAF (2005) A conserved checkpoint monitors meiotic chromosome synapsis in Caenorhabditis elegans. Science 310 : 1683–1686.
72. AshleyT, GaethAP, CreemersLB, HackAM, de RooijDG (2004) Correlation of meiotic events in testis sections and microspreads of mouse spermatocytes relative to the mid-pachytene checkpoint. Chromosoma 113 : 126–136.
73. BurgoynePS, MahadevaiahSK, TurnerJM (2009) The consequences of asynapsis for mammalian meiosis. Nature reviews Genetics 10 : 207–216.
74. PetersAH, PlugAW, van VugtMJ, de BoerP (1997) A drying-down technique for the spreading of mammalian meiocytes from the male and female germline. Chromosome research 5 : 66–68.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
