Metaphase is marked by the formation of the metaphase plate. The metaphase plate is formed when the spindle fibers align the chromosomes along the middle of the cell. Such an organization helps to ensure that later, when the chromosomes are separated, each new nucleus that is formed receives one copy of each chromosome. This pathway has not yet been annotated in Reactome.
The metaphase to anaphase transition during mitosis is triggered by the destruction of mitotic cyclins.
In anaphase, the paired chromosomes separate at the centromeres, and move to the opposite sides of the cell. The movement of the chromosomes is facilitated by a combination of kinetochore movement along the spindle microtubules and through the physical interaction of polar microtubules.
View original pathway at Reactome.
Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J.; ''Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1.''; PubMedEurope PMCScholia
Hetzer M, Bilbao-Cortés D, Walther TC, Gruss OJ, Mattaj IW.; ''GTP hydrolysis by Ran is required for nuclear envelope assembly.''; PubMedEurope PMCScholia
Olmos Y, Hodgson L, Mantell J, Verkade P, Carlton JG.; ''ESCRT-III controls nuclear envelope reformation.''; PubMedEurope PMCScholia
Bernier-Villamor V, Sampson DA, Matunis MJ, Lima CD.; ''Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1.''; PubMedEurope PMCScholia
Lee GW, Melchior F, Matunis MJ, Mahajan R, Tian Q, Anderson P.; ''Modification of Ran GTPase-activating protein by the small ubiquitin-related modifier SUMO-1 requires Ubc9, an E2-type ubiquitin-conjugating enzyme homologue.''; PubMedEurope PMCScholia
Jin L, Williamson A, Banerjee S, Philipp I, Rape M.; ''Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex.''; PubMedEurope PMCScholia
Rasala BA, Orjalo AV, Shen Z, Briggs S, Forbes DJ.; ''ELYS is a dual nucleoporin/kinetochore protein required for nuclear pore assembly and proper cell division.''; PubMedEurope PMCScholia
Schwartz M, Travesa A, Martell SW, Forbes DJ.; ''Analysis of the initiation of nuclear pore assembly by ectopically targeting nucleoporins to chromatin.''; PubMedEurope PMCScholia
Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ.; ''Proteomic analysis of the mammalian nuclear pore complex.''; PubMedEurope PMCScholia
Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, Melmed S.; ''Structure, expression, and function of human pituitary tumor-transforming gene (PTTG).''; PubMedEurope PMCScholia
Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, De Baere E, Decroos C, Di Donato N, Ernst S, Francey LJ, Gyftodimou Y, Hirashima K, Hullings M, Ishikawa Y, Jaulin C, Kaur M, Kiyono T, Lombardi PM, Magnaghi-Jaulin L, Mortier GR, Nozaki N, Petersen MB, Seimiya H, Siu VM, Suzuki Y, Takagaki K, Wilde JJ, Willems PJ, Prigent C, Gillessen-Kaesbach G, Christianson DW, Kaiser FJ, Jackson LG, Hirota T, Krantz ID, Shirahige K.; ''HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.''; PubMedEurope PMCScholia
Moshe Y, Boulaire J, Pagano M, Hershko A.; ''Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome.''; PubMedEurope PMCScholia
Jallepalli PV, Waizenegger IC, Bunz F, Langer S, Speicher MR, Peters JM, Kinzler KW, Vogelstein B, Lengauer C.; ''Securin is required for chromosomal stability in human cells.''; PubMedEurope PMCScholia
Schmitz MH, Held M, Janssens V, Hutchins JR, Hudecz O, Ivanova E, Goris J, Trinkle-Mulcahy L, Lamond AI, Poser I, Hyman AA, Mechtler K, Peters JM, Gerlich DW.; ''Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells.''; PubMedEurope PMCScholia
Tseng LC, Chen RH.; ''Temporal control of nuclear envelope assembly by phosphorylation of lamin B receptor.''; PubMedEurope PMCScholia
Mahajan R, Delphin C, Guan T, Gerace L, Melchior F.; ''A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2.''; PubMedEurope PMCScholia
Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMedEurope PMCScholia
Vietri M, Schink KO, Campsteijn C, Wegner CS, Schultz SW, Christ L, Thoresen SB, Brech A, Raiborg C, Stenmark H.; ''Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing.''; PubMedEurope PMCScholia
Zhang C, Clarke PR.; ''Roles of Ran-GTP and Ran-GDP in precursor vesicle recruitment and fusion during nuclear envelope assembly in a human cell-free system.''; PubMedEurope PMCScholia
Haraguchi T, Kojidani T, Koujin T, Shimi T, Osakada H, Mori C, Yamamoto A, Hiraoka Y.; ''Live cell imaging and electron microscopy reveal dynamic processes of BAF-directed nuclear envelope assembly.''; PubMedEurope PMCScholia
Zou H, McGarry TJ, Bernal T, Kirschner MW.; ''Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis.''; PubMedEurope PMCScholia
Franz C, Walczak R, Yavuz S, Santarella R, Gentzel M, Askjaer P, Galy V, Hetzer M, Mattaj IW, Antonin W.; ''MEL-28/ELYS is required for the recruitment of nucleoporins to chromatin and postmitotic nuclear pore complex assembly.''; PubMedEurope PMCScholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
Mitchell JM, Mansfeld J, Capitanio J, Kutay U, Wozniak RW.; ''Pom121 links two essential subcomplexes of the nuclear pore complex core to the membrane.''; PubMedEurope PMCScholia
Dultz E, Zanin E, Wurzenberger C, Braun M, Rabut G, Sironi L, Ellenberg J.; ''Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells.''; PubMedEurope PMCScholia
Asencio C, Davidson IF, Santarella-Mellwig R, Ly-Hartig TB, Mall M, Wallenfang MR, Mattaj IW, Gorjánácz M.; ''Coordination of kinase and phosphatase activities by Lem4 enables nuclear envelope reassembly during mitosis.''; PubMedEurope PMCScholia
Plafker SM, Plafker KS, Weissman AM, Macara IG.; ''Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import.''; PubMedEurope PMCScholia
Waizenegger I, Giménez-Abián JF, Wernic D, Peters JM.; ''Regulation of human separase by securin binding and autocleavage.''; PubMedEurope PMCScholia
Ventimiglia LN, Cuesta-Geijo MA, Martinelli N, Caballe A, Macheboeuf P, Miguet N, Parnham IM, Olmos Y, Carlton JG, Weissenhorn W, Martin-Serrano J.; ''CC2D1B Coordinates ESCRT-III Activity during the Mitotic Reformation of the Nuclear Envelope.''; PubMedEurope PMCScholia
Anderson DJ, Vargas JD, Hsiao JP, Hetzer MW.; ''Recruitment of functionally distinct membrane proteins to chromatin mediates nuclear envelope formation in vivo.''; PubMedEurope PMCScholia
Knipscheer P, Flotho A, Klug H, Olsen JV, van Dijk WJ, Fish A, Johnson ES, Mann M, Sixma TK, Pichler A.; ''Ubc9 sumoylation regulates SUMO target discrimination.''; PubMedEurope PMCScholia
Gu M, LaJoie D, Chen OS, von Appen A, Ladinsky MS, Redd MJ, Nikolova L, Bjorkman PJ, Sundquist WI, Ullman KS, Frost A.; ''LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells.''; PubMedEurope PMCScholia
Kaufmann T, Kukolj E, Brachner A, Beltzung E, Bruno M, Kostrhon S, Opravil S, Hudecz O, Mechtler K, Warren G, Slade D.; ''SIRT2 regulates nuclear envelope reassembly through ANKLE2 deacetylation.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Bischoff FR, Klebe C, Kretschmer J, Wittinghofer A, Ponstingl H.; ''RanGAP1 induces GTPase activity of nuclear Ras-related Ran.''; PubMedEurope PMCScholia
Hauf S, Waizenegger IC, Peters JM.; ''Cohesin cleavage by separase required for anaphase and cytokinesis in human cells.''; PubMedEurope PMCScholia
Hsiao HH, Meulmeester E, Frank BT, Melchior F, Urlaub H.; ''"ChopNSpice," a mass spectrometric approach that allows identification of endogenous small ubiquitin-like modifier-conjugated peptides.''; PubMedEurope PMCScholia
Waizenegger IC, Hauf S, Meinke A, Peters JM.; ''Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase.''; PubMedEurope PMCScholia
Lu X, Shi Y, Lu Q, Ma Y, Luo J, Wang Q, Ji J, Jiang Q, Zhang C.; ''Requirement for lamin B receptor and its regulation by importin {beta} and phosphorylation in nuclear envelope assembly during mitotic exit.''; PubMedEurope PMCScholia
Hauf S, Roitinger E, Koch B, Dittrich CM, Mechtler K, Peters JM.; ''Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2.''; PubMedEurope PMCScholia
The dissolution of the nuclear membrane marks the beginning of the prometaphase. Kinetochores are created when proteins attach to the centromeres. Microtubules then attach at the kinetochores, and the chromosomes begin to move to the metaphase plate.
During the early stages of mitosis, Cdc2 and PLK1 cooperate to phosphorylate Emi1 and this modification induces Emi1 degradation through a Skp1-Cullin1 F-box protein (SCF) ubiquitin ligase-mediated proteolysis. Degradation of Emi1 permits activation of anaphase promoting complex and thereby the onset of anaphase.
After APC/C-mediated degradation of PTTG1 (securin), ESPL1 (separin i.e. separase) is rapidly autocatalytically cleaved after arginine residues at positions 1506 and 1535. The N-terminal and C-terminal fragments remain bound to each other after cleavage. It has not been examined what happens with the short middle fragment of ESPL1, so it is annotated as a part of the autocleaved ESPL1 complex. The autocatalytic cleavage of ESPL1 is not a prerequisite for the subsequent cleavage of the cohesin subunit RAD21 (Waizenegger et al. 2002).
Up to anaphase onset, ESPL1 (separase i.e. separin) forms a complex with PTTG1 (pituitary tumor-transforming gene 1) i.e. securin. PTTG1 sequesters ESPL1 and block its catalytic site, preventing it from cleaving centromeric cohesin and causing premature separation of sister chromatids (Zou et al. 1999, Waizenegger et al. 2001, Waizenegger et al. 2002). PTTG1 is overexpressed in cancer and acts as an oncogene (Zhang et al. 1999). Regulation of PTTG1 cellular level is important for chromosomal stability in human cells (Jallepalli et al. 2001).
ESPL1 (separin i.e. separase) cleaves RAD21 (SCC1) subunit of centromeric cohesin at two sites that conform to the consensus separase recognition site E-X-X-R: after arginine residue R172 and after arginine residue R450 (Hauf et al. 2001). Phosphorylation of RAD21 at the serine residue S454 by PLK1 in prometaphase facilitates ESPL1-mediated cleavage of RAD21 at the C-terminal cleavage site R450 (Hauf et al. 2005). The N-terminal and C-terminal RAD21 cleavage fragments remain bound to the rest of the cohesin complex (Deardorff et al. 2012). It is not clear whether RAD21 middle fragment also continues to be associated with cohesin.
The cleavage of RAD21 subunit of centromeric cohesin by ESPL1 (separin i.e. separase) promotes dissociation of cohesin complexes from centromeric chromatin at the onset of anaphase, allowing for sister chromatid separation and segregation of replicated chromosomes to daughter cells (Waizenegger et al. 2000, Hauf et al. 2001, Waizenegger et al. 2002).
Histone deacetylase HDAC8 deacetylates SMC3 cohesin subunit. SMC3 deacetylation promotes dissociation of cleaved RAD21 fragments from other cohesin proteins and their replacement with intact RAD21, thereby allowing restoration of the cohesin complex (Deardorff et al. 2012). HDAC8 mutations, as well as mutations in NIPBL, SMC1A and SMC3, can cause Cornelia de Lang syndrome (Deardorff et al. 2012).
In late anaphase/early telophase, the separated sister chromatids usually coalesce into a single "chromatin disc". At the surface of the chromatin disc, there is an accumulation of dephosphorylated BANF1 (BAF) (Kaufmann et al. 2016), as well as proteins EMD (emerin), TMPO (LAP2beta), LEMD3 (MAN1), LEMD2 (LEM2) and lamins (Haraguchi et al. 2008, Asencio et al. 2012). Collectively, these interactions promote enclosure of the separated sister chromatids with nuclear membranes (Anderson et al. 2009).
The PP2A complex that contains the regulatory subunit PPP2R2A (B55-alpha) is the only phosphatase essential for mitotic exit (Schmitz et al. 2010). It is also necessary for BANF1 (BAF) dephosphorylation in anaphase/telophase. ANKLE2 binds the PP2A complex that contains the B55-alpha regulatory subunit and facilitates BANF1 dephosphorylation (Asencio et al. 2012).
Both human ANKLE2 and the C. elegans ortholog LEM4 bind VRK1 (and possibly VRK2), the kinase responsible for phosphorylation of BANF1 (BAF) in mitotic prophase, and inhibit VRK1 catalytic activity (Asencio et al. 2012).
The majority of RANGAP1 in the cell is conjugated with SUMO1 by the E3 ligase UBE2l (Ubc9) (Knipscheer et al. 1998, Lee et al. 1998). SUMO1 targets RANGAP1 to the nucleoporin RANBP2 (Mahajan et al. 1997).
Based on studies in human and Xenopus model systems (Rasala et al. 2006, Franz et al. 2007, Gillespie et al. 2007), and C. elegans (Fernandez and Piano 2006) model systems, the chromatin binding protein AHCTF1 (ELYS, MEL-28) selectively interacts with the Nup107-160 complex and acts as a seeding center for assembly of nuclear pore complexes (NPCs) at the chromatin surface in late anaphase/telophase. In the absence of AHCTF1, the nuclear envelope can re-assemble but lacks NPCs (Francz et al. 2007).
After disassembly of the NPC in prophase, the Nup107-160 complex is sequestered through interaction with transportin (TPNO1) and/or importin-beta (KPNB1), as suggested by studies with Xenopus egg extracts and recombinant human proteins (Lau et al. 2009, Bernis et al. 2014), and in cultured human cells. Binding to TPNO1 and/or KPNB1 prevents Nup107-160 association with chromatin prior to the onset of NE reassembly.
Based on studies with recombinant human proteins and Xenopus egg extracts, RAN:GTP binds to transportin (TNPO1) or importin beta (KPNB1) associated with the Nup107-160 complex (Lau et al. 2009), resulting in release of the latter.
Based on studies in Xenopus (Fichtman et al. 2010) and human (Schwartz et al. 2015) models, POM121 binds the Nup107-160 complex through direct interaction with NUP133, a subunit of the Nup107-160 complex. Binding of POM121 to the Nup107-160 complex precedes formation of the nuclear pore diffusion barrier (Dultz et al. 2008), and is followed by recruitment of FG repeat nucleoporins (Fichtman et al. 2010). FG nucleoporins contain phenylalanine-glycine repeats needed for interaction with soluble nuclear import and export receptors (Frey et al. 2006).
Phosphorylation of LBR (lamin B receptor) at serine residue S71 drives binding of LBR to KPNB1 (importin beta) (Lu et al. 2010). This prevents premature association of nascent nuclear membranes with chromatin in anaphase (Tseng and Chen 2011). Dephosphorylation of this site is suggested to promote NE reassembly (Tseng and Chen 2011).
During mitosis, CDK1 phosphorylates LBR (lamin B receptor) on N-terminal serine residues S71 and S86. S71 is the major CDK1 phosphorylation site in LBR (Tseng and Chen 2011).
Chromatin-associated RCC1 mediates GDP to GTP exchange on RAN, resulting in formation of the active RAN:GTP complex (Hetzer et al. 2000, reviewed by Zierhut and Funabiki 2015). The high concentration of RAN:GTP near chromatin promotes multiple aspects of nuclear envelope reassembly (reviewed by Forbes et al. 2015). RAN:GDP may be involved in recruitment of RCC1 to chromatin (Zhang et al. 2002).
RAN:GTP is required for recruitment of membrane vesicles to chromatin during NE reassembly with an in vitro system (Zhang and Clarke 2001). This process could involve actions of RAN:GTP on many targets (reviewed by Forbes et al. 2015).
From studies with Xenopus and human model systems, the transmembrane nucleoporins POM121 and NDC1 recruit the NUP93 complex to nascent nuclear pore complexes (NPCs) due to interaction with the NUP93 complex components NUP155 (Mitchell et al. 2010) and, potentially, NUP35 (Mansfield et al. 2006). This is consistent with order-of-assembly seen in live cell imaging (Dultz et al. 2008).
The N-terminal domain of NUP93, the eponymous subunit of the Nup93 complex, recruits the Nup62 complex, consisting of phenylglycine (FG) repeat-containing nucleoporins NUP62, NUP58 and NUP54 (Chug et al. 2015), to the nascent nuclear pore complex (NPC) (Sachdev et al. 2012). The barrier function of the NPC is reestablished at this point (Dultz et al. 2008).
ANKLE2 (LEM4) is required for normal nuclear envelope (NE) formation at the end of mitosis (Ascencio et al. 2012, Kaufmann et al. 2016). Deacetylation of ANKLE2 on residue K302 by SIRT2 promotes this process (Kaufman et al. 2016).
The ESCRT-III subunit CHMP7 binds LEMD2 (LEM2) at holes in the reforming nuclear envelope that are juxtaposed to the chromatin surface (Vietri et al 2015, Gu et al 2017).
CHMP7 binding to CC2D1B temporally coordinates ESCRT-III assembly/disassembly with the microtubule severing activity of spastin (SPAST) (Ventimiglia et al. 2018).
CHMP7 promotes the assembly of other ESCRT-III subunits at nuclear envelope fenestrations. It first binds CHMP4B, which in turn causes recruitment and assembly of other ESCRTIII subunits including CHMP2A, CHMP4A, CHMP3 and IST1 (Olmos et al. 2015, Vietri et al. 2015, Gu et al. 2017).
The AAA+ ATPase action of VPS4 causes reorganization/disassembly of ESCRT-III filaments, which leads to membrane fusion and sealing of nuclear envelope holes (Vietri et al. 2015).
The AAA+ ATPase activity of spastin (SPAST) removes attached microtubules from chromosomes, allowing formation of a sealed nuclear envelope (Vietri et al. 2015, Ventimiglia et al. 2018).
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complex:Nup93
complex:NUP188:NDC1:POM121:AHCTF1:ChromatinAnnotated Interactions
complex:Nup93
complex:NUP188:NDC1:POM121:AHCTF1:Chromatin