Dissociation of membrane–chromatin contacts is required for proper chromosome segregation in mitosis

Champion, Lysie; Pawar, Sumit; Luithle, Naemi; Ungricht, Rosemarie; Kutay, Ulrike

doi:10.1091/mbc.e18-10-0609

Cited by 34 publications

(47 citation statements)

References 60 publications

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“…Alternatively, or additionally, passive ER exclusion by spindle microtubules is thought to occur when mitotic phosphorylation of ERmicrotubule linking proteins disrupts their interaction with the spindle [7,12]. While the importance of ER membrane exclusion from the spindle is not clearly established, it has been proposed to facilitate movement of mitotic chromosomes [11,13], including metaphase chromosome congression and anaphase segregation of chromosomes [14] (Figure 1(b-c)).…”

Section: Introductionmentioning

confidence: 99%

The coordination of nuclear envelope assembly and chromosome segregation in metazoans

Liu

Pellman

2020

Nucleus

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The nuclear envelope (NE) is composed of two lipid bilayer membranes that enclose the eukaryotic genome. In interphase, the NE is perforated by thousands of nuclear pore complexes (NPCs), which allow transport in and out of the nucleus. During mitosis in metazoans, the NE is broken down and then reassembled in a manner that enables proper chromosome segregation and the formation of a single nucleus in each daughter cell. Defects in coordinating NE reformation and chromosome segregation can cause aberrant nuclear architecture. This includes the formation of micronuclei, which can trigger a catastrophic mutational process commonly observed in cancers called chromothripsis. Here, we discuss the current understanding of the coordination of NE reformation with chromosome segregation during mitotic exit in metazoans. We review differing models in the field and highlight recent work suggesting that normal NE reformation and chromosome segregation are physically linked through the timing of mitotic spindle disassembly.

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Section: Introductionmentioning

confidence: 99%

The coordination of nuclear envelope assembly and chromosome segregation in metazoans

Liu

Pellman

2020

Nucleus

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“…In the course of prophase, the multifaceted interactions between INM proteins, chromatin and nuclear lamins are broken, allowing for the separation of membranes from chromatin and the partitioning of INM proteins into the mitotic ER network (Ellenberg et al, 1997, Yang et al, 1997. Exploiting a synthetic membrane-chromatin tethering system, we recently demonstrated that failed removal of membranes from chromatin impairs mitotic chromatin organization, chromosome segregation and cytokinesis, and perturbs post-mitotic nuclear morphology (Champion et al, 2019). Notably, also in yeasts with closed mitosis, the detachment of chromosomes from the NE is required for faithful chromosome segregation (Titos et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Also chromatin-associated interaction partners of INM proteins such as BAF are released from chromatin by mitotic phosphorylation (Samwer et al, 2017). After prophase, multiple mechanisms ensure that the ER does not re-associate with chromatin prematurely, before NE reformation starts in late anaphase (Champion et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Torsin ATPases influence chromatin interaction of the Torsin regulator LAP1

Luithle

Bos

Hovius

et al. 2020

Preprint

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The inner nuclear membrane is functionalized by diverse transmembrane proteins that associate with nuclear lamins and/or chromatin. When cells enter mitosis, membrane-chromatin contacts must be broken to allow for proper chromosome segregation; yet how this occurs remains ill-understood. Unexpectedly, we observed that an imbalance in the levels of the lamina-associated polypeptide 1 (LAP1), an activator of ER-resident Torsin AAA+-ATPases, causes a failure in membrane removal from mitotic chromatin, accompanied by chromosome segregation errors and changes in post-mitotic nuclear morphology. These defects are dependent on a hitherto unknown chromatin-binding region of LAP1 that we have delineated. LAP1-induced NE abnormalities are efficiently suppressed by expression of wild-type but not ATPase-deficient Torsins. Furthermore, a dominant-negative Torsin induces chromosome segregation defects in a LAP1-dependent manner. These results indicate that association of LAP1 with chromatin in the nucleus can be modulated by Torsins in the perinuclear space, shedding new light on the LAP1-Torsin interplay.

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“…The release of chromosomes from the NE, whether through breakdown of the NE or dissociation from an intact membrane, is a common feature of mitosis in eukaryotes 38–41 . Indeed, in cultured human cells, the artificial tethering of histones to ER membranes leads to chromatin bridges and failure in chromosome segregation and chromatin organisation 44 . Our data indicate that ESCRT-III/AAA-ATPase Vps4 functions to release heterochromatin from the INM and this active process is critical for normal progression through mitosis.…”

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confidence: 99%

ESCRT-III/Vps4 controls heterochromatin-nuclear envelope attachments

Pieper

Sprenger

Teis

et al. 2019

Preprint

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23In eukaryotes chromosomes are compartmentalized within the nucleus 24 delimited by the double membrane of the nuclear envelope (NE). Defects in the 25 function and structure of the NE are linked to disease 1,2 . During interphase, the 26 NE organizes the genome and regulates its expression 3 . As cells enter mitosis, 27 chromosomes are released from the NE, which is then remodelled to form the 28 daughter nuclei at mitotic exit 4 . Interactions between the NE and chromatin 29 underpinning both interphase and post-mitotic NE functions are executed by 30 inner nuclear membrane (INM) proteins such as members of the evolutionarily 31 conserved chromatin-binding LEM-domain family 5-8 . How chromatin tethering 32 by these transmembrane proteins is controlled in interphase and if such a 33 regulation contributes to subsequent NE dynamics in mitosis remains unclear. 34 Here we probe these fundamental questions using an emerging model 35 organism, the fission yeast Schizosaccharomyces japonicus, which breaks 36 and reforms the NE during mitosis 9,10 . We show that attachments between 37 heterochromatin and the transmembrane Lem2-Nur1 complex are 38 continuously remodelled in interphase by the ESCRT-III/AAA-ATPase Vps4 39 machinery. ESCRT-III/Vps4 mediates the release of Lem2-Nur1 from 40 heterochromatin as a prerequisite for the timely progression through mitosis. 41 Failure in this process leads to persistent association of chromosomes with 42 the INM, which prevents Lem2-Nur1 from re-localizing to the sites of NE 43 sealing around the mitotic spindle and severely delays re-establishment of 44 nucleocytoplasmic compartmentalization. Our work establishes the INM 45 transmembrane Lem2-Nur1 complex as a 'substrate' for ESCRT-III/Vps4 to 46 couple dynamic tethering of chromosomes to the INM with the establishment 47(SPB) localization 10 (Fig. 1a). Other NE proteins such as components of the nuclear 57 pore complexes (NPCs) and the second fission yeast LEM-domain protein Man1 are 58 largely excluded from the 'tails' due to their interactions with segregating 59 chromosomes at this stage of mitosis 10-12 . Thus, the 'tail' is a specialized membrane 60 domain, spatially segregated and partitioned away from the rest of the NE during 61 mitotic exit (Fig. 1a, right panel). 62 63 Lem2 orthologues function in complex with another INM protein Nur1 to promote 64 heterochromatin tethering and heterochromatic gene silencing [13][14][15] . In S. japonicus, 65Nur1 largely co-localized with Lem2 throughout the cell cycle, enriching at the NE 66 'tails' at the end of mitosis (Fig. 1b). This localization of Nur1 required Lem2, as Nur1 67 redistributed throughout the ER in lem2∆ cells (Fig. 1c). Conversely, in cells lacking 68 Nur1, less Lem2 signal was detected at the SPBs and the NE (Fig. 1d). Additionally, 69Lem2 residence time at the 'tails' was drastically reduced in Nur1-defcient cells (Fig. 70 1e). Thus, Lem2 and Nur1 appear to co-depend on each other for proper localization 71 to the NE and the SPB throughout the cell cycle. 72 73...

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Dissociation of membrane–chromatin contacts is required for proper chromosome segregation in mitosis

Cited by 34 publications

References 60 publications

The coordination of nuclear envelope assembly and chromosome segregation in metazoans

The coordination of nuclear envelope assembly and chromosome segregation in metazoans

Torsin ATPases influence chromatin interaction of the Torsin regulator LAP1

ESCRT-III/Vps4 controls heterochromatin-nuclear envelope attachments

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