Phosphorylation of Chromosome Core Components May Serve as Axis Marks for the Status of Chromosomal Events during Mammalian Meiosis
Meiotic recombination and chromosome synapsis between homologous chromosomes are essential for proper chromosome segregation at the first meiotic division. While recombination and synapsis, as well as checkpoints that monitor these two events, take place in the context of a prophase I-specific axial chromosome structure, it remains unclear how chromosome axis components contribute to these processes. We show here that many protein components of the meiotic chromosome axis, including SYCP2, SYCP3, HORMAD1, HORMAD2, SMC3, STAG3, and REC8, become post-translationally modified by phosphorylation during the prophase I stage. We found that HORMAD1 and SMC3 are phosphorylated at a consensus site for the ATM/ATR checkpoint kinase and that the phosphorylated forms of HORMAD1 and SMC3 localize preferentially to unsynapsed chromosomal regions where synapsis has not yet occurred, but not to synapsed or desynapsed regions. We investigated the genetic requirements for the phosphorylation events and revealed that the phosphorylation levels of HORMAD1, HORMAD2, and SMC3 are dramatically reduced in the absence of initiation of meiotic recombination, whereas BRCA1 and SYCP3 are required for normal levels of phosphorylation of HORMAD1 and HORMAD2, but not of SMC3. Interestingly, reduced HORMAD1 and HORMAD2 phosphorylation is associated with impaired targeting of the MSUC (meiotic silencing of unsynapsed chromatin) machinery to unsynapsed chromosomes, suggesting that these post-translational events contribute to the regulation of the synapsis surveillance system. We propose that modifications of chromosome axis components serve as signals that facilitate chromosomal events including recombination, checkpoint control, transcription, and synapsis regulation.
Vyšlo v časopise:
Phosphorylation of Chromosome Core Components May Serve as Axis Marks for the Status of Chromosomal Events during Mammalian Meiosis. PLoS Genet 8(2): e32767. doi:10.1371/journal.pgen.1002485
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002485
Souhrn
Meiotic recombination and chromosome synapsis between homologous chromosomes are essential for proper chromosome segregation at the first meiotic division. While recombination and synapsis, as well as checkpoints that monitor these two events, take place in the context of a prophase I-specific axial chromosome structure, it remains unclear how chromosome axis components contribute to these processes. We show here that many protein components of the meiotic chromosome axis, including SYCP2, SYCP3, HORMAD1, HORMAD2, SMC3, STAG3, and REC8, become post-translationally modified by phosphorylation during the prophase I stage. We found that HORMAD1 and SMC3 are phosphorylated at a consensus site for the ATM/ATR checkpoint kinase and that the phosphorylated forms of HORMAD1 and SMC3 localize preferentially to unsynapsed chromosomal regions where synapsis has not yet occurred, but not to synapsed or desynapsed regions. We investigated the genetic requirements for the phosphorylation events and revealed that the phosphorylation levels of HORMAD1, HORMAD2, and SMC3 are dramatically reduced in the absence of initiation of meiotic recombination, whereas BRCA1 and SYCP3 are required for normal levels of phosphorylation of HORMAD1 and HORMAD2, but not of SMC3. Interestingly, reduced HORMAD1 and HORMAD2 phosphorylation is associated with impaired targeting of the MSUC (meiotic silencing of unsynapsed chromatin) machinery to unsynapsed chromosomes, suggesting that these post-translational events contribute to the regulation of the synapsis surveillance system. We propose that modifications of chromosome axis components serve as signals that facilitate chromosomal events including recombination, checkpoint control, transcription, and synapsis regulation.
Zdroje
1. KeeneyS 2001 Mechanism and control of meiotic recombination initiation. Curr Top Dev Biol 52 1 53
2. RomanienkoPJCamerini-OteroRD 2000 The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 6 975 987
3. BaudatFManovaKYuenJPJasinMKeeneyS 2000 Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell 6 989 998
4. ZicklerDKlecknerN 1999 Meiotic chromosomes: integrating structure and function. Annu Rev Genet 33 603 754
5. PageSLHawleyRS 2004 The genetics and molecular biology of the synaptonemal complex. Annu Rev Cell Dev Biol 20 525 558
6. PetronczkiMSiomosMFNasmythK 2003 Un menage a quatre: the molecular biology of chromosome segregation in meiosis. Cell 112 423 440
7. HochwagenAAmonA 2006 Checking your breaks: surveillance mechanisms of meiotic recombination. Curr Biol 16 R217 228
8. BarchiMMahadevaiahSDi GiacomoMBaudatFde RooijDG 2005 Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Mol Cell Biol 25 7203 7215
9. Di GiacomoMBarchiMBaudatFEdelmannWKeeneyS 2005 Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci USA 102 737 742
10. BurgoynePSMahadevaiahSKTurnerJM 2009 The consequences of asynapsis for mammalian meiosis. Nat Rev Genet 10 207 216
11. HandelMASchimentiJC 2010 Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11 124 136
12. Fernandez-CapetilloOMahadevaiahSKCelesteARomanienkoPJCamerini-OteroRD 2003 H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 4 497 508
13. TurnerJMMahadevaiahSKFernandez-CapetilloONussenzweigAXuX 2005 Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet 37 41 47
14. MahadevaiahSKBourc'hisDde RooijDGBestorTHTurnerJM 2008 Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. J Cell Biol 182 263 276
15. RoyoHPolikiewiczGMahadevaiahSKProsserHMitchellM 2010 Evidence that meiotic sex chromosome inactivation is essential for male fertility. Curr Biol 20 2117 2123
16. DanielKLangeJHachedKFuJAnastassiadisK 2011 Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1. Nat Cell Biol 13 599 610
17. BellaniMARomanienkoPJCairattiDACamerini-OteroRD 2005 SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm−/− spermatocytes. J Cell Sci 118 3233 3245
18. SujaJABarberoJL 2009 Cohesin complexes and sister chromatid cohesion in mammalian meiosis. Genome Dyn 5 94 116
19. LeeJHiranoT 2011 RAD21L, a novel cohesin subunit implicated in linking homologous chromosomes in mammalian meiosis. J Cell Biol 192 263 276
20. IshiguroKKimJFujiyama-NakamuraSKatoSWatanabeY 2011 A new meiosis-specific cohesin complex implicated in the cohesin code for homologous pairing. EMBO Rep 12 267 275
21. HerranYGutierrez-CaballeroCSanchez-MartinMHernandezTVieraA 2011 The cohesin subunit RAD21L functions in meiotic synapsis and exhibits sexual dimorphism in fertility. EMBO J 30 3091 3105
22. KurodaMOikawaKOhbayashiTYoshidaKYamadaK 2005 A dioxin sensitive gene, mammalian WAPL, is implicated in spermatogenesis. FEBS Lett 579 167 172
23. FukudaTHoogC 2010 Mouse cohesin-associated protein PDS5B is expressed in testicular cells and is associated with the meiotic chromosome axes. Genes 1 484 494
24. YuanLLiuJGZhaoJBrundellEDaneholtB 2000 The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell 5 73 83
25. YangFDe La FuenteRLeuNABaumannCMcLaughlinKJ 2006 Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J Cell Biol 173 497 507
26. FukudaTDanielKWojtaszLTothAHoogC 2010 A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes. Exp Cell Res 316 158 171
27. WojtaszLDanielKRoigIBolcun-FilasEXuH 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 doi:10.1371/journal.pgen.1000702
28. LuoHLiYMuJJZhangJTonakaT 2008 Regulation of intra-S phase checkpoint by ionizing radiation (IR)-dependent and IR-independent phosphorylation of SMC3. J Biol Chem 283 19176 19183
29. BarlowCLiyanageMMoensPBTarsounasMNagashimaK 1998 Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125 4007 4017
30. ForayNMarotDGabrielARandrianarisonVCarrAM 2003 A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. EMBO J 22 2860 2871
31. TurnerJMAprelikovaOXuXWangRKimS 2004 BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation. Curr Biol 14 2135 2142
32. XuXAprelikovaOMoensPDengCXFurthPA 2003 Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Development 130 2001 2012
33. de VriesFAde BoerEvan den BoschMBaarendsWMOomsM 2005 Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev 19 1376 1389
34. HamerGWangHBolcun-FilasECookeHJBenaventeR 2008 Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J Cell Sci 121 2445 2451
35. RevenkovaEEijpeMHeytingCHodgesCAHuntPA 2004 Cohesin SMC1β is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat Cell Biol 6 555 562
36. LiebeBAlsheimerMHoogCBenaventeRScherthanH 2004 Telomere attachment, meiotic chromosome condensation, pairing, and bouquet stage duration are modified in spermatocytes lacking axial elements. Mol Biol Cell 15 827 837
37. PelttariJHojaMRYuanLLiuJGBrundellE 2001 A meiotic chromosomal core consisting of cohesin complex proteins recruits DNA recombination proteins and promotes synapsis in the absence of an axial element in mammalian meiotic cells. Mol Cell Biol 21 5667 5677
38. ShinYHChoiYErdinSUYatsenkoSAKlocM 2010 Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis. PLoS Genet 6 e1001190 doi:10.1371/journal.pgen.1001190
39. MahadevaiahSKTurnerJMBaudatFRogakouEPde BoerP 2001 Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet 27 271 276
40. HamerGNovakIKouznetsovaAHoogC 2008 Disruption of pairing and synapsis of chromosomes causes stage-specific apoptosis of male meiotic cells. Theriogenology 69 333 339
41. LammersJHvan AalderenMPetersAHvan PeltAAde RooijDG 1995 A change in the phosphorylation pattern of the 30000–33000 Mr synaptonemal complex proteins of the rat between early and mid-pachytene. Chromosoma 104 154 163
42. PrietoISujaJAPezziNKremerLMartinezAC 2001 Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I. Nat Cell Biol 3 761 766
43. LeeJIwaiTYokotaTYamashitaM 2003 Temporally and spatially selective loss of Rec8 protein from meiotic chromosomes during mammalian meiosis. J Cell Sci 116 2781 2790
44. EijpeMOffenbergHJessbergerRRevenkovaEHeytingC 2003 Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3. J Cell Biol 160 657 670
45. BannisterLAReinholdtLGMunroeRJSchimentiJC 2004 Positional cloning and characterization of mouse mei8, a disrupted allelle of the meiotic cohesin Rec8. Genesis 40 184 194
46. XuHBeasleyMDWarrenWDvan der HorstGTMcKayMJ 2005 Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev Cell 8 949 961
47. WangHHoogC 2006 Structural damage to meiotic chromosomes impairs DNA recombination and checkpoint control in mammalian oocytes. J Cell Biol 173 485 495
48. HaufSRoitingerEKochBDittrichCMMechtlerK 2005 Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2. PLoS Biol 3 e69 doi:10.1371/journal.pbio.0060069
49. CarballoJAJohnsonALSedgwickSGChaRS 2008 Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination. Cell 132 758 770
50. BrarGAHochwagenAEeLSAmonA 2009 The multiple roles of cohesin in meiotic chromosome morphogenesis and pairing. Mol Biol Cell 20 1030 1047
51. JamesRDSchmiesingJAPetersAHYokomoriKDistecheCM 2002 Differential association of SMC1α and SMC3 proteins with meiotic chromosomes in wild-type and SPO11-deficient male mice. Chromosome Res 10 549 560
52. WatrinEPetersJM 2009 The cohesin complex is required for the DNA damage-induced G2/M checkpoint in mammalian cells. EMBO J 28 2625 2635
53. WassmannKLiberalVBenezraR 2003 Mad2 phosphorylation regulates its association with Mad1 and the APC/C. EMBO J 22 797 806
54. LiXCBolcun-FilasESchimentiJC 2011 Genetic evidence that synaptonemal complex axial elements govern recombination pathway choice in mice. Genetics 189 71 82
55. WattsFZHoffmannE 2011 SUMO meets meiosis: An encounter at the synaptonemal complex: SUMO chains and sumoylated proteins suggest that heterogeneous and complex interactions lie at the centre of the synaptonemal complex. Bioessays 33 529 537
56. LiXCSchimentiJC 2007 Mouse pachytene checkpoint 2 (Trip13) is required for completing meiotic recombination but not synapsis. PLoS Genet 3 e130 doi:10.1371/journal.pgen.0030130
57. XuXQiaoWLinkeSPCaoLLiWM 2001 Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 28 266 271
58. KouznetsovaANovakIJessbergerRHoogC 2005 SYCP2 and SYCP3 are required for cohesin core integrity at diplotene but not for centromere cohesion at the first meiotic division. J Cell Sci 118 2271 2278
59. PetersAHPlugAWvan VugtMJde BoerP 1997 A drying-down technique for the spreading of mammalian meiocytes from the male and female germline. Chromosome Res 5 66 68
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 2
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Gene Expression and Stress Response Mediated by the Epigenetic Regulation of a Transposable Element Small RNA
- Contrasting Properties of Gene-Specific Regulatory, Coding, and Copy Number Mutations in : Frequency, Effects, and Dominance
- Homeobox Genes Critically Regulate Embryo Implantation by Controlling Paracrine Signaling between Uterine Stroma and Epithelium
- Nondisjunction of a Single Chromosome Leads to Breakage and Activation of DNA Damage Checkpoint in G2