Cyclin B3 Is Required for Multiple Mitotic Processes Including Alleviation of a Spindle Checkpoint–Dependent Block in Anaphase Chromosome Segregation
The master regulators of the cell cycle are cyclin-dependent kinases (Cdks), which influence the function of a myriad of proteins via phosphorylation. Mitotic Cdk1 is activated by A-type, as well as B1- and B2-type, cyclins. However, the role of a third, conserved cyclin B family member, cyclin B3, is less well defined. Here, we show that Caenorhabditis elegans CYB-3 has essential and distinct functions from cyclin B1 and B2 in the early embryo. CYB-3 is required for the timely execution of a number of cell cycle events including completion of the MII meiotic division of the oocyte nucleus, pronuclear migration, centrosome maturation, mitotic chromosome condensation and congression, and, most strikingly, progression through the metaphase-to-anaphase transition. Our experiments reveal that the extended metaphase delay in CYB-3–depleted embryos is dependent on an intact spindle assembly checkpoint (SAC) and results in salient defects in the architecture of holocentric metaphase chromosomes. Furthermore, genetically increasing or decreasing dynein activity results in the respective suppression or enhancement of CYB-3–dependent defects in cell cycle progression. Altogether, these data reveal that CYB-3 plays a unique, essential role in the cell cycle including promoting mitotic dynein functionality and alleviation of a SAC–dependent block in anaphase chromosome segregation.
Vyšlo v časopise:
Cyclin B3 Is Required for Multiple Mitotic Processes Including Alleviation of a Spindle Checkpoint–Dependent Block in Anaphase Chromosome Segregation. PLoS Genet 6(11): e32767. doi:10.1371/journal.pgen.1001218
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001218
Souhrn
The master regulators of the cell cycle are cyclin-dependent kinases (Cdks), which influence the function of a myriad of proteins via phosphorylation. Mitotic Cdk1 is activated by A-type, as well as B1- and B2-type, cyclins. However, the role of a third, conserved cyclin B family member, cyclin B3, is less well defined. Here, we show that Caenorhabditis elegans CYB-3 has essential and distinct functions from cyclin B1 and B2 in the early embryo. CYB-3 is required for the timely execution of a number of cell cycle events including completion of the MII meiotic division of the oocyte nucleus, pronuclear migration, centrosome maturation, mitotic chromosome condensation and congression, and, most strikingly, progression through the metaphase-to-anaphase transition. Our experiments reveal that the extended metaphase delay in CYB-3–depleted embryos is dependent on an intact spindle assembly checkpoint (SAC) and results in salient defects in the architecture of holocentric metaphase chromosomes. Furthermore, genetically increasing or decreasing dynein activity results in the respective suppression or enhancement of CYB-3–dependent defects in cell cycle progression. Altogether, these data reveal that CYB-3 plays a unique, essential role in the cell cycle including promoting mitotic dynein functionality and alleviation of a SAC–dependent block in anaphase chromosome segregation.
Zdroje
1. SanchezI
DynlachtBD
2005 New insights into cyclins, CDKs, and cell cycle control. Semin Cell Dev Biol 16 311 321
2. ArchambaultV
ChangEJ
DrapkinBJ
CrossFR
ChaitBT
2004 Targeted proteomic study of the cyclin-Cdk module. Mol Cell 14 699 711
3. BlethrowJD
GlavyJS
MorganDO
ShokatKM
2008 Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates. Proc Natl Acad Sci U S A 105 1442 1447
4. SantaguidaS
MusacchioA
2009 The life and miracles of kinetochores. EMBO J 28 2511 2531
5. DernburgAF
2001 Here, there, and everywhere: kinetochore function on holocentric chromosomes. J Cell Biol 153 F33 38
6. BlackBE
BassettEA
2008 The histone variant CENP-A and centromere specification. Curr Opin Cell Biol 20 91 100
7. MusacchioA
SalmonED
2007 The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8 379 393
8. MarescaTJ
SalmonED
2009 Intrakinetochore stretch is associated with changes in kinetochore phosphorylation and spindle assembly checkpoint activity. J Cell Biol 184 373 381
9. WatersJC
ChenRH
MurrayAW
SalmonED
1998 Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J Cell Biol 141 1181 1191
10. EssexA
DammermannA
LewellynL
OegemaK
DesaiA
2009 Systematic analysis in Caenorhabditis elegans reveals that the spindle checkpoint is composed of two largely independent branches. Mol Biol Cell 20 1252 1267
11. AhonenLJ
KallioMJ
DaumJR
BoltonM
MankeIA
2005 Polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores. Curr Biol 15 1078 1089
12. RuchaudS
CarmenaM
EarnshawWC
2007 Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 8 798 812
13. DeLucaJG
GallWE
CiferriC
CiminiD
MusacchioA
2006 Kinetochore microtubule dynamics and attachment stability are regulated by Hec1. Cell 127 969 982
14. CheesemanIM
ChappieJS
Wilson-KubalekEM
DesaiA
2006 The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127 983 997
15. AndrewsPD
OvechkinaY
MorriceN
WagenbachM
DuncanK
2004 Aurora B regulates MCAK at the mitotic centromere. Dev Cell 6 253 268
16. BakhoumSF
ThompsonSL
ManningAL
ComptonDA
2009 Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat Cell Biol 11 27 35
17. PinskyBA
KungC
ShokatKM
BigginsS
2006 The Ipl1-Aurora protein kinase activates the spindle checkpoint by creating unattached kinetochores. Nat Cell Biol 8 78 83
18. VanoosthuyseV
HardwickKG
2009 Overcoming inhibition in the spindle checkpoint. Genes Dev 23 2799 2805
19. LiuD
VaderG
VromansMJ
LampsonMA
LensSM
2009 Sensing chromosome bi-orientation by spatial separation of aurora B kinase from kinetochore substrates. Science 323 1350 1353
20. HowellBJ
McEwenBF
CanmanJC
HoffmanDB
FarrarEM
2001 Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J Cell Biol 155 1159 1172
21. GriffisER
StuurmanN
ValeRD
2007 Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore. J Cell Biol 177 1005 1015
22. SchmidtDJ
RoseDJ
SaxtonWM
StromeS
2005 Functional analysis of cytoplasmic dynein heavy chain in Caenorhabditis elegans with fast-acting temperature-sensitive mutations. Mol Biol Cell 16 1200 1212
23. SivaramMV
WadzinskiTL
RedickSD
MannaT
DoxseySJ
2009 Dynein light intermediate chain 1 is required for progress through the spindle assembly checkpoint. EMBO J 28 902 914
24. GallantP
NiggEA
1994 Identification of a novel vertebrate cyclin: cyclin B3 shares properties with both A- and B-type cyclins. EMBO J 13 595 605
25. NguyenTB
ManovaK
CapodieciP
LindonC
BottegaS
2002 Characterization and expression of mammalian cyclin b3, a prepachytene meiotic cyclin. J Biol Chem 277 41960 41969
26. MilesDC
van den BergenJA
SinclairAH
WesternPS
2010 Regulation of the female mouse germ cell cycle during entry into meiosis. Cell Cycle 9 408 418
27. JacobsHW
KnoblichJA
LehnerCF
1998 Drosophila Cyclin B3 is required for female fertility and is dispensable for mitosis like Cyclin B. Genes Dev 12 3741 3751
28. McClelandML
FarrellJA
O'FarrellPH
2009 Influence of cyclin type and dose on mitotic entry and progression in the early Drosophila embryo. J Cell Biol 184 639 646
29. SonnichsenB
KoskiLB
WalshA
MarschallP
NeumannB
2005 Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 434 462 469
30. van der VoetM
LorsonMA
SrinivasanDG
BennettKL
van den HeuvelS
2009 C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation. Cell Cycle 8 4091 4102
31. SonnevilleR
GonczyP
2004 Zyg-11 and cul-2 regulate progression through meiosis II and polarity establishment in C. elegans. Development 131 3527 3543
32. LyczakR
ZweierL
Group T, Murrow MA, Snyder C, et al. 2006 The puromycin-sensitive aminopeptidase PAM-1 is required for meiotic exit and anteroposterior polarity in the one-cell Caenorhabditis elegans embryo. Development 133 4281 4292
33. ShirayamaM
SotoMC
IshidateT
KimS
NakamuraK
2006 The Conserved Kinases CDK-1, GSK-3, KIN-19, and MBK-2 Promote OMA-1 Destruction to Regulate the Oocyte-to-Embryo Transition in C. elegans. Curr Biol 16 47 55
34. OegemaK
HymanAA
2006 Cell division. WormBook 1 40
35. OegemaK
DesaiA
RybinaS
KirkhamM
HymanAA
2001 Functional analysis of kinetochore assembly in Caenorhabditis elegans. J Cell Biol 153 1209 1226
36. McNallyK
AudhyaA
OegemaK
McNallyFJ
2006 Katanin controls mitotic and meiotic spindle length. J Cell Biol 175 881 891
37. GonczyP
SchnabelH
KalettaT
AmoresAD
HymanT
1999 Dissection of cell division processes in the one cell stage Caenorhabditis elegans embryo by mutational analysis. J Cell Biol 144 927 946
38. KimDY
RoyR
2006 Cell cycle regulators control centrosome elimination during oogenesis in Caenorhabditis elegans. J Cell Biol 174 751 757
39. AlbertsonDG
1984 Formation of the first cleavage spindle in nematode embryos. Dev Biol 101 61 72
40. ShakesDC
SadlerPL
SchumacherJM
AbdolrasulniaM
GoldenA
2003 Developmental defects observed in hypomorphic anaphase-promoting complex mutants are linked to cell cycle abnormalities. Development 130 1605 1620
41. HachetV
CanardC
GonczyP
2007 Centrosomes promote timely mitotic entry in C. elegans embryos. Dev Cell 12 531 541
42. PortierN
AudhyaA
MaddoxPS
GreenRA
DammermannA
2007 A microtubule-independent role for centrosomes and aurora a in nuclear envelope breakdown. Dev Cell 12 515 529
43. MainsPE
KemphuesKJ
SprungerSA
SulstonIA
WoodWB
1990 Mutations affecting the meiotic and mitotic divisions of the early Caenorhabditis elegans embryo. Genetics 126 593 605
44. SchumacherJM
GoldenA
DonovanPJ
1998 AIR-2: An Aurora/Ipl1-related protein kinase associated with chromosomes and midbody microtubules is required for polar body extrusion and cytokinesis in Caenorhabditis elegans embryos. J Cell Biol 143 1635 1646
45. AshcroftNR
SraykoM
KosinskiME
MainsPE
GoldenA
1999 RNA-Mediated interference of a cdc25 homolog in Caenorhabditis elegans results in defects in the embryonic cortical membrane, meiosis, and mitosis. Dev Biol 206 15 32
46. SeversonAF
LingL
van ZuylenV
MeyerBJ
2009 The axial element protein HTP-3 promotes cohesin loading and meiotic axis assembly in C. elegans to implement the meiotic program of chromosome segregation. Genes Dev 23 1763 1778
47. KitagawaR
RoseAM
1999 Components of the spindle-assembly checkpoint are essential in Caenorhabditis elegans. Nat Cell Biol 1 514 521
48. KitagawaR
2009 The spindle assembly checkpoint in Caenorhabditis elegans: one who lacks Mad1 becomes mad one. Cell Cycle 8 338 344
49. NystulTG
GoldmarkJP
PadillaPA
RothMB
2003 Suspended animation in C. elegans requires the spindle checkpoint. Science 302 1038 1041
50. EncaladaSE
WillisJ
LyczakR
BowermanB
2005 A spindle checkpoint functions during mitosis in the early Caenorhabditis elegans embryo. Mol Biol Cell 16 1056 1070
51. HagstromKA
HolmesVF
CozzarelliNR
MeyerBJ
2002 C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis. Genes Dev 16 729 742
52. MaddoxPS
OegemaK
DesaiA
CheesemanIM
2004 “Holo”er than thou: chromosome segregation and kinetochore function in C. elegans. Chromosome Res 12 641 653
53. MooreLL
MorrisonM
RothMB
1999 HCP-1, a protein involved in chromosome segregation, is localized to the centromere of mitotic chromosomes in Caenorhabditis elegans. J Cell Biol 147 471 480
54. MooreLL
RothMB
2001 HCP-4, a CENP-C-like protein in Caenorhabditis elegans, is required for resolution of sister centromeres. J Cell Biol 153 1199 1208
55. MaddoxPS
HyndmanF
MonenJ
OegemaK
DesaiA
2007 Functional genomics identifies a Myb domain-containing protein family required for assembly of CENP-A chromatin. J Cell Biol 176 757 763
56. CheesemanIM
NiessenS
AndersonS
HyndmanF
YatesJR3rd
2004 A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev 18 2255 2268
57. BuchwitzBJ
AhmadK
MooreLL
RothMB
HenikoffS
1999 A histone-H3-like protein in C. elegans. Nature 401 547 548
58. DesaiA
RybinaS
Muller-ReichertT
ShevchenkoA
HymanA
2003 KNL-1 directs assembly of the microtubule-binding interface of the kinetochore in C. elegans. Genes Dev 17 2421 2435
59. ShapiroPS
VaisbergE
HuntAJ
TolwinskiNS
WhalenAM
1998 Activation of the MKK/ERK pathway during somatic cell mitosis: direct interactions of active ERK with kinetochores and regulation of the mitotic 3F3/2 phosphoantigen. J Cell Biol 142 1533 1545
60. DaumJR
GorbskyGJ
1998 Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha, which is recognized by the 3F3/2 phosphoepitope antibody. J Biol Chem 273 30622 30629
61. ShannonKB
CanmanJC
SalmonED
2002 Mad2 and BubR1 function in a single checkpoint pathway that responds to a loss of tension. Mol Biol Cell 13 3706 3719
62. CallegariAJ
KellyTJ
2007 Shedding light on the DNA damage checkpoint. Cell Cycle 6 660 666
63. KeoghMC
KimJA
DowneyM
FillinghamJ
ChowdhuryD
2006 A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery. Nature 439 497 501
64. BaderJR
VaughanKT
2010 Dynein at the kinetochore: Timing, Interactions and Functions. Semin Cell Dev Biol 21 269 275
65. GassmannR
EssexA
HuJS
MaddoxPS
MotegiF
2008 A new mechanism controlling kinetochore-microtubule interactions revealed by comparison of two dynein-targeting components: SPDL-1 and the Rod/Zwilch/Zw10 complex. Genes Dev 22 2385 2399
66. BishopJD
HanZ
SchumacherJM
2005 The Caenorhabditis elegans Aurora B kinase AIR-2 phosphorylates and is required for the localization of a BimC kinesin to meiotic and mitotic spindles. Mol Biol Cell 16 742 756
67. O'RourkeSM
DorfmanMD
CarterJC
BowermanB
2007 Dynein modifiers in C. elegans: light chains suppress conditional heavy chain mutants. PLoS Genet 3 e128 doi:10.1371/journal.pgen.0030128
68. GonczyP
PichlerS
KirkhamM
HymanAA
1999 Cytoplasmic dynein is required for distinct aspects of MTOC positioning, including centrosome separation, in the one cell stage Caenorhabditis elegans embryo. J Cell Biol 147 135 150
69. RobinsonJT
WojcikEJ
SandersMA
McGrailM
HaysTS
1999 Cytoplasmic dynein is required for the nuclear attachment and migration of centrosomes during mitosis in Drosophila. J Cell Biol 146 597 608
70. SalinaD
BodoorK
EckleyDM
SchroerTA
RattnerJB
2002 Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell 108 97 107
71. StearJH
RothMB
2002 Characterization of HCP-6, a C. elegans protein required to prevent chromosome twisting and merotelic attachment. Genes Dev 16 1498 1508
72. LoncarekJ
Kisurina-EvgenievaO
VinogradovaT
HergertP
La TerraS
2007 The centromere geometry essential for keeping mitosis error free is controlled by spindle forces. Nature 450 745 749
73. SillerKH
SerrM
StewardR
HaysTS
DoeCQ
2005 Live imaging of Drosophila brain neuroblasts reveals a role for Lis1/dynactin in spindle assembly and mitotic checkpoint control. Mol Biol Cell 16 5127 5140
74. WalczakCE
HealdR
2008 Mechanisms of mitotic spindle assembly and function. Int Rev Cytol 265 111 158
75. PinskyBA
NelsonCR
BigginsS
2009 Protein phosphatase 1 regulates exit from the spindle checkpoint in budding yeast. Curr Biol 19 1182 1187
76. DeMoeJH
SantaguidaS
DaumJR
MusacchioA
GorbskyGJ
2009 A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor. Cancer Res 69 1509 1516
77. VanoosthuyseV
HardwickKG
2009 A novel protein phosphatase 1-dependent spindle checkpoint silencing mechanism. Curr Biol 19 1176 1181
78. McClelandML
O'FarrellPH
2008 RNAi of mitotic cyclins in Drosophila uncouples the nuclear and centrosome cycle. Curr Biol 18 245 254
79. MorganDO
2010 The hidden rhythms of the dividing cell. Cell 141 224 226
80. LuY
CrossFR
2010 Periodic cyclin-Cdk activity entrains an autonomous Cdc14 release oscillator. Cell 141 268 279
81. HamillDR
SeversonAF
CarterJC
BowermanB
2002 Centrosome Maturation and Mitotic Spindle Assembly in C. elegans Require SPD-5, a Protein with Multiple Coiled-Coil Domains. Dev Cell 3 673 684
82. YoderJH
HanM
2001 Cytoplasmic dynein light intermediate chain is required for discrete aspects of mitosis in Caenorhabditis elegans. Mol Biol Cell 12 2921 2933
83. BrennerS
1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94
84. GoldenA
LiuJ
Cohen-FixO
2009 Inactivation of the C. elegans lipin homolog leads to ER disorganization and to defects in the breakdown and reassembly of the nuclear envelope. J Cell Sci 122 1970 1978
85. TarailoM
KitagawaR
RoseAM
2007 Suppressors of spindle checkpoint defect (such) mutants identify new mdf-1/MAD1 interactors in Caenorhabditis elegans. Genetics 175 1665 1679
86. DumontJ
OegemaK
DesaiA
2010 A kinetochore-independent mechanism drives anaphase chromosome separation during acentrosomal meiosis. Nat Cell Biol 12 894 901
87. MaddoxPS
PortierN
DesaiA
OegemaK
2006 Molecular analysis of mitotic chromosome condensation using a quantitative time-resolved fluorescence microscopy assay. Proc Natl Acad Sci U S A 103 15097 15102
88. KamathRS
AhringerJ
2003 Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30 313 321
89. SeydouxG
DunnMA
1997 Transcriptionally repressed germ cells lack a subpopulation of phosphorylated RNA polymerase II in early embryos of Caenorhabditis elegans and Drosophila melanogaster. Development 124 2191 2201
90. MonenJ
MaddoxPS
HyndmanF
OegemaK
DesaiA
2005 Differential role of CENP-A in the segregation of holocentric C. elegans chromosomes during meiosis and mitosis. Nat Cell Biol 7 1248 1255
91. DinkelmannMV
ZhangH
SkopAR
WhiteJG
2007 SPD-3 is required for spindle alignment in Caenorhabditis elegans embryos and localizes to mitochondria. Genetics 177 1609 1620
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
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