Repair of nuclear ruptures requires barrier-to-autointegration factor

Halfmann, Charles; Sears, Rhiannon M.; Katiyar, Aditya; Busselman, Brook W.; Aman, London; Zhang, Qiao; O’Bryan, Christopher S.; Angelini, Thomas E.; Lele, Tanmay P.; Roux, Kyle J.

doi:10.1083/jcb.201901116

Cited by 142 publications

(254 citation statements)

References 60 publications

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“…where it is tethered to the membrane by the LEM proteins. Such a scenario is consistent with a recently suggested model for BAF involvement in repair of mechanically induced membrane rupture (Halfmann et al, 2019). In both cases, recruitment of cytoplasmic BAF to the nuclear membrane is sensitive to changes in the mechanical properties of the nuclear membrane, and then, due to interaction with LEM proteins, BAF becomes localized to the inner nuclear membrane.…”

Section: Discussionsupporting

confidence: 90%

“…Previous experiments indicated that BAF does not diffuse passively from the cytoplasm to the nucleus (Shimi et al, 2004). Furthermore, photobleaching experiments with GFP-BAF indicated that BAF-dependent repair of nuclear ruptures occurs when cytoplasmic BAF, but not internal nuclear BAF, is recruited to the ruptured sites, and this further brings LEM domain proteins that are essential for membrane sealing (Halfmann et al, 2019). These findings are consistent with a dynamic exchange between cytoplasmic and nuclear BAF, in which BAF in the cytoplasm primarily responds to mechanical signals.…”

Section: Discussionmentioning

confidence: 97%

“…Its interaction with both dsDNA and the nuclear lamina enables DNA compaction through cross-bridges between chromosomes and the nuclear membrane, a process that is essential for the formation of a single nucleus following mitosis (Samwer et al, 2017). Likewise, BAF is recruited to sites of ruptured nuclear membrane, where it is essential for sealing of these ruptures (Halfmann et al, 2019). Interestingly, in humans a single amino acid substitution of BAF causes Nestor-Guillermo progeria syndrome (NGPS) (Puente et al, 2011); however, the molecular basis for the disease awaits further investigation.…”

Section: Introductionmentioning

confidence: 99%

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Mechanosensitive recruitment of BAF to the nuclear membrane inhibits nuclear E2F1 and Yap levels

Unnikannan

Reuveny

Grunberg

et al. 2019

Preprint

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Mechanotransduction has been implicated as an important factor in regulating cell cycle progression; however, the underlying mechanism has not been fully elucidated.Here, we describe a novel mechano-sensitive component, namely barrier to autointegration factor, (BAF), which regulates DNA endocycling in Drosophila muscle fibers. We show that BAF negatively regulates DNA endoreplication by inhibiting of the nuclear entrance of E2F1 and Yap/Yorkie, two key components in cell cycle control. Furthermore, BAF localization at the nuclear membrane is mechanosensitive, as it was downregulated in LINC mutant larval muscles, or following nuclear deformation caused by disruption of nucleus-sarcomere connections. BAF forms a protein complex with E2F1, which is sensitive to BAF phosphorylation. Knockdown of BAF kinase VRK1/Ball disrupted localization of BAF at the nuclear membrane and resulted in increased E2F1 nuclear levels. Taken together, our results reveal a novel mechanosensitive pathway controlling BAF phosphorylation and localization at the nuclear membrane, which in turn, represses nuclear accumulation of positive cell cycle regulators.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanosensitive recruitment of BAF to the nuclear membrane inhibits nuclear E2F1 and Yap levels

Unnikannan

Reuveny

Grunberg

et al. 2019

Preprint

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“…It is plausible that transient changes in NE organization at NE rupture sites may signal or support membrane insertion (De Vos et al, 2011;Denais et al, 2016;Raab et al, 2016;Penfield et al, 2018). For instance, BAF crosslinks chromatin at the core region of chromatin that coincides with spindle microtubules (Samwer et al, 2017) and was recently shown to accumulate at rupture sites (Halfmann et al, 2019), providing a possible mechanism to direct membrane incorporation to this region. Identifying how ER sheets are delivered into NE holes in different contexts is an important next step.…”

Section: Resultsmentioning

confidence: 99%

“…In interphase, NE ruptures that cause rapid mixing of nuclear and cytoplasmic components, and at times nuclear entry of whole organelles, depend on ESCRT-III for resealing (De vos et al, 2011;Vargas et al, 2012;Denais et al, 2016;Raab et al, 2016). Even micron-scale punctures caused by lasers undergo slow repair (Denais et al, 2016;Penfield et al, 2018;Halfmann et al, 2019). Given the evidence that the ESCRT-III spiral filament (VPS-32/Snf7/CHMP4B) resolves holes of ~30-50 nm in diameter (Wollert and Hurley, 2010;McCullough et al, 2018;Olmos et al, 2015;, mechanisms must exist to narrow large membrane holes in interphase NE ruptures and during NE reformation before ESCRT-III acts.…”

Section: Introductionmentioning

confidence: 99%

Local regulation of lipid synthesis controls ER sheet insertion into nuclear envelope holes to complete nuclear closure

Penfield

Shankar

Szentgyörgyi

et al. 2019

Preprint

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The nuclear permeability barrier depends on closure of holes in the nuclear envelope (NE). Here, we use meiotic C. elegans oocytes to demonstrate that local control of glycerophospholipid synthesis by CNEP-1/CTDNEP1 regulates the insertion of ER sheets into NE holes and functions independently of ESCRT-III to ensure NE closure.Deletion of CNEP-1 causes excess incorporation of ER membranes into NE holes and a defective NE permeability barrier. ESCRT-III components accumulate at the NE opening surrounding the meiotic spindle, and loss of NE adaptors for ESCRT-III exacerbates NE sealing defects in cnep-1 mutants. Limiting ER sheet production by restoring glycerophospholipid synthesis in cnep-1 mutants rescued NE permeability defects. 3D analysis showed that membrane sheets feed into and narrow NE holes occluded by meiotic spindle microtubules supporting a role for ER sheet insertion in NE closure.Thus, feeding of ER sheets into NE holes must be coordinated with production of ER sheets near the NE to promote NE closure.

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The Nucleus Bypasses Obstacles by Deforming Like a Drop with Surface Tension Mediated by Lamin A/C

et al. 2022

Self Cite

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Migrating cells must deform their stiff cell nucleus to move through pores and fibers in tissue. Lamin A/C is known to hinder cell migration by limiting nuclear deformation and passage through confining channels, but its role in nuclear deformation and passage through fibrous environments is less clear. Cell and nuclear migration through discrete, closely spaced, slender obstacles which mimic the mechanical properties of collagen fibers are studied. Nuclei bypass slender obstacles while preserving their overall morphology by deforming around them with deep local invaginations of little resisting force. The obstacles do not impede the nuclear trajectory and do not cause rupture of the nuclear envelope. Nuclei likewise deform around single collagen fibers in cells migrating in 3D collagen gels. In contrast to its limiting role in nuclear passage through confining channels, lamin A/C facilitates nuclear deformation and passage through fibrous environments; nuclei in lamin‐null ( Lmna −/− ) cells lose their overall morphology and become entangled on the obstacles. Analogous to surface tension‐mediated deformation of a liquid drop, lamin A/C imparts a surface tension on the nucleus that allows nuclear invaginations with little mechanical resistance, preventing nuclear entanglement and allowing nuclear passage through fibrous environments.

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Repair of nuclear ruptures requires barrier-to-autointegration factor

Cited by 142 publications

References 60 publications

Mechanosensitive recruitment of BAF to the nuclear membrane inhibits nuclear E2F1 and Yap levels

Mechanosensitive recruitment of BAF to the nuclear membrane inhibits nuclear E2F1 and Yap levels

Local regulation of lipid synthesis controls ER sheet insertion into nuclear envelope holes to complete nuclear closure

The Nucleus Bypasses Obstacles by Deforming Like a Drop with Surface Tension Mediated by Lamin A/C

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