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The chromosome (segregation: mitosis and meiosis)

The chromosome (segregation: mitosis and meiosis). Thierry Voet ( Thierry.Voet@med.kuleuven.be ). Intro: DNA molecules are packaged into thread-like structures called chromosomes. Non-histone proteins. 147bp DNA. Linker DNA (10 bp – 60 bp ). basic unit of chromosomes =.

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The chromosome (segregation: mitosis and meiosis)

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  1. The chromosome (segregation: mitosis and meiosis) Thierry Voet (Thierry.Voet@med.kuleuven.be)

  2. Intro: DNA molecules are packaged into thread-like structures called chromosomes Non-histoneproteins 147bp DNA Linker DNA (10 bp – 60 bp) basic unit of chromosomes = Interphase nucleus

  3. Humans: 46 chromosomes

  4. Chromosomes are carriers of genetic info, and are important for correct transport and integrity of genetic information

  5. Mitosis and meiosis

  6. Mitosis and meiosis

  7. Metaphase Anaphase Prometaphase Telophase Prophase Cytokinesis Interphase DNA tubulin

  8. Metaphase Anaphase Prometaphase Telophase Prophase Cytokinesis Interphase

  9. Metaphase Anaphase Prometaphase Telophase Prophase Cytokinesis Interphase

  10. Loss of sister chromatid cohesion during mitosis

  11. Loss of sister chromatid cohesion during mitosis Pro(meta)phase Metaphase Cohesin complex Anaphase Metaphase

  12. Loss of sister chromatid cohesion during mitosis Pro(meta)phase Metaphase Anaphase Metaphase

  13. Prometaphase Metaphase

  14. Loss of sister chromatid cohesion during mitosis Pro(meta)phase Metaphase Anaphase Metaphase

  15. Pericentric human HP1 interacts with human Sgo1

  16. Pericentric human HP1 interacts with human Sgo1 Nature 2008; 455: 251-255

  17. Loss of sister chromatid cohesion during mitosis Pro(meta)phase Metaphase Anaphase Metaphase No premature loss of sister chromatidcohesion

  18. Physical dislocation of Sgo-PP2A allows phosphorylation and separase-mediated cleavage of centromericcohesin

  19. Correct release of the cohesin complex is mediated by the spindle assembly checkpoint (SAC) MCC Musacchio and Salmon, Nature Reviews MCB (2007); 8: 379-393

  20. Most popular model for the molecular basis of SAC function (1) MCC Anaphase (APC/C; separase)

  21. Most popular model for the molecular basis of SAC function (1) MCC Anaphase (APC/C; separase)

  22. Most popular model for the molecular basis of SAC function (2) Anaphase (APC/C; separase)

  23. Most popular model for the molecular basis of SAC function (2) Anaphase (APC/C; separase)

  24. Chromosomes ensure transport and integrity of genetic information Centromere • correct segregation • (capture microtubules) • - chromosome movements Telomeres • protectagainstdegradation, fusion and recombination • complete end replication • chromosome movements • subtelomeric gene expression Origins of replication - replication of the genetic information once per cell cycle Sister chromatids Functional domains Kinetochore Microtubules

  25. Molecularplayers of functionalcentromeres

  26. Centromeric DNA: Alpha-satellite or alphoid DNA at normal human chromosomes

  27. Centromeric DNA: Alpha-satellite or alphoid DNA at normal human chromosomes 20-40% sequence divergence <2% sequence divergence • Alpha-satellite higherorderrepeatscanbe: • specificfor a single chromosome • resideon differentchromosomes • Differentalpha-satellite higherorderrepeatscanexist on the same chromosome

  28. Alpha-satellite DNA does not determinecentromerefunction A.Pseudodicentricchromosomes withnative centromeresequence: inactivation of one alpha-satellite centromere B. Neo-centromeres on euchromatic DNA Neocentromeer formatie Centromerefunctionisepigeneticallyregulated

  29. Histone H3 variant CENP-A is the best candidate to carry the epigenetic centromere mark Localised centromeres Diffuse centromeres FEBS Letters 582 (2008) 1950–1959

  30. CENP-A is found at active centromeres Current Opinion in Cell Biology 2008, 20:91–100

  31. CENP-A provides special nucleosomal properties and recruits the CENP-ANAC (Nucleosome Associated Complex) Homotypic Heterotypic CENP-A nucleosomes Functional difference between homotypic and heterotypic CENP-A nucleosomes? Heterotypic nucleosomes respresent a transient form during the genesis of homotypic nucleosomes? Current Opinion in Cell Biology 2008, 20:91–100

  32. Achieving higher-order chromatin structure at the centromere Current Opinion in Cell Biology 2008, 20:91–100

  33. Higher-orderchromatin structure: chromatinsubdomainswithin the centromeres are characterized by different histone modifications & differentfunctions FEBS Letters 582 (2008) 1950–1959

  34. Chromosomes ensure transport and integrity of genetic information Centromere • correct segregation • (capture microtubules) • - chromosome movements Telomeres • protectagainstdegradation, fusion and recombination • complete end replication • chromosome movements • subtelomeric gene expression Origins of replication - replication of the genetic information once per cell cycle Sister chromatids Functional domains Kinetochore Microtubules

  35. Chromosomes ensure transport and integrity of genetic information Centromere • correct segregation • (capture microtubules) • - chromosome movements Telomeres • protectagainstdegradation, fusion and recombination • complete end replication • chromosome movements • subtelomeric gene expression Origins of replication - replication of the genetic information once per cell cycle Sister chromatids Functional domains DSB Kinetochore Nucleoproteincomplex: (TTAGGG)n + shelterin Microtubules

  36. Chromosomes ensure transport and integrity of genetic information Centromere • correct segregation • (capture microtubules) • - chromosome movements Telomeres • protectagainstdegradation, fusion and recombination • complete end replication • chromosome movements • subtelomeric gene expression U Origins of replication A - replication of the genetic information once per cell cycle Sister chromatids Functional domains Kinetochore Nucleoproteincomplex: (TTAGGG)n + shelterin Microtubules

  37. The meiotic story…

  38. Meiosis: Greek for ‘to reduce’ Diploidsomaticcell (2n) Chromosomes replicated once meiosis I: reductional division - separation of homologous autosomes - separation of sex chromosomes meiosis II: equational division separation of sister chromatids (~mitosis) Haploidgametes 4 x (n)

  39. Meiosis I: Sister chromatid cohesin complexes distal from the chiasmata hold the homologues together to oppose to the spindle forces Prophase I: homologous chrs align, pair, synaps and recombine Anaphase I Metaphase I Centromere Telomere Chiasmata Meiosis I Sister chromatids Cohesin complex

  40. Meiosis II: Centromeric cohesin complexes hold the sister chromatids together to oppose to the spindle forces Metaphase II Haploid sperm Meiosis II

  41. Physical dislocation of Sgo-PP2A allows phosphorylation and separase-mediated cleavage of centromericcohesin

  42. The spindleassemblycheckpoint in meiosis Vogt et al. Mutation Research 651 (2008) 14-29

  43. The spindleassemblycheckpoint in meiosis Vogt et al. Mutation Research 651 (2008) 14-29

  44. To generatechiasmata (genetic cross-overs) duringmeiosis I, prophase I is lengthy and canbesubdivided in different stages: 1.Leptonema 2.Zygonema 3.Pachynema 4.Diplonema SC DSB Genetic crossover Bouquet formation DSB

  45. mitosis DSB meiosis Duringleptonema of prophase I meioticcellsdeliberatelydamage their DNA using SPO11 Sister chromatids of replicated maternal homologue Sister chromatids of replicated paternal homologue Cohesin complex (SMC1 / SMC3 / REC8 / STAG3 SMC1 / SMC3 / REC8 / STAG3 SMC1 / SMC3 / RAD21 / SA1/2) SPO11

  46. More than 200 DSBs are created in leptonema, the majority of these are repaired as non-crossovers Spo11 Maternalchromatid Rad51 Dmc1 RPA Paternalchromatid Mlh1 Mlh3 Synthesis-dependent strand annealing Whitby (2005) Biochemical Society Transactions, 33:1451-1455

  47. Mus81 pathway (mainly active in fission yeast) isalsooperational in mammals Mus81-/- are fertile, but… Holloway et al. (2008) PlosGenetics, 4: e1000186

  48. Formation of bivalents: homologous chromosomes zippered together by the synaptonemal complex Synaptonemal complex Axial/lateral element (SCP2 / SCP3) mitosis Transverse filaments (SCP1) meiosis Sister chromatids of replicated maternal homologue Sister chromatids of replicated paternal homologue Cohesin complex (SMC1 / SMC3 / REC8 / STAG3 SMC1 / SMC3 / REC8 / STAG3 SMC1 / SMC3 / RAD21 / SA1/2) DSB

  49. Analysis of prophase I : DSB formation and repairprocess / Homologue pairing and synapsis (H2AX– SCP3 -DNAstaining) Leptonema

  50. Analysis of prophase I : DSB formation and repair process / Homologue pairing and synapsis (Rad51 – SCP3 -DNAstaining) Early leptonema

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