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1. Transcription inhibition suppresses nuclear blebbing and rupture independent of nuclear rigidity

   https://doi.org/10.1242/jcs.261547  

   Berg, Isabel K.; Currey, Marilena L.; Gupta, Sarthak; Berrada, Yasmin; Nguyen, Bao V.; Pho, Mai; Patteson, Alison E.; Schwarz, J. M.; Banigan, Edward J.; Stephens, Andrew D. (September 2023, Journal of Cell Science)

   Chromatin is an essential component of nuclear mechanical response and shape that maintains nuclear compartmentalization and function. However, major genomic functions, such as transcription activity, might also impact cell nuclear shape via blebbing and rupture through their effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with several RNA polymerase II inhibitors in wild type cells and perturbed cells that present increased nuclear blebbing. Transcription inhibition suppresses nuclear blebbing for several cell types, nuclear perturbations, and transcription inhibitors. Furthermore, transcription inhibition suppresses nuclear bleb formation, bleb stabilization, and bleb-based nuclear ruptures. Interestingly, transcription inhibition does not alter either H3K9 histone modification state, nuclear rigidity, or actin compression and contraction, which typically control nuclear blebbing. Polymer simulations suggest that RNA pol II motor activity within chromatin could drive chromatin motions that deform the nuclear periphery. Our data provide evidence that transcription inhibition suppresses nuclear blebbing and rupture, separate and distinct from chromatin rigidity. 

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2. Mechanosensitive nuclear uptake of chemotherapy

   https://doi.org/10.1126/sciadv.adr5947  

   Scott, Nicholas R; Kang, Sowon; Parekh, Sapun H (December 2024, Science Advances)

   The nucleus is at the nexus of mechanotransduction and the final barrier for most first line chemotherapeutics. Here, we study the intersection between nuclear-cytoskeletal coupling and chemotherapy nuclear internalization. We find that chronic and acute modulation of intracellular filaments changes nuclear influx of doxorubicin (DOX). Rapid changes in cell strain by disruption of cytoskeletal and nuclear filaments sensitize nuclei to DOX, whereas chronic reduction of cell strain desensitize nuclei to DOX. Extracted nuclei from invasive cancer cells lines from different tissues have distinct nuclear permeability to DOX. Last, we show that mechano-priming of cells by paclitaxel markedly improves DOX nuclear internalization, rationalizing the observed drug synergies. Our findings reveal that nuclear uptake is a critical, previously unquantified aspect of drug resistance. With nuclear permeability to chemotherapy being tunable via modulation of nuclear mechanotransduction, mechano-priming may be useful to help overcome drug resistance in the future. 

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3. Practical phase-space electronic Hamiltonians for ab initio dynamics

   https://doi.org/10.1063/5.0192084  

   Tao, Zhen; Qiu, Tian; Bhati, Mansi; Bian, Xuezhi; Duston, Titouan; Rawlinson, Jonathan; Littlejohn, Robert G; Subotnik, Joseph E (March 2024, The Journal of Chemical Physics)

   Modern electronic structure theory is built around the Born–Oppenheimer approximation and the construction of an electronic Hamiltonian Ĥel(X) that depends on the nuclear position X (and not the nuclear momentum P). In this article, using the well-known theory of electron translation (Γ′) and rotational (Γ″) factors to couple electronic transitions to nuclear motion, we construct a practical phase-space electronic Hamiltonian that depends on both nuclear position and momentum, ĤPS(X,P). While classical Born–Oppenheimer dynamics that run along the eigensurfaces of the operator Ĥel(X) can recover many nuclear properties correctly, we present some evidence that motion along the eigensurfaces of ĤPS(X,P) can better capture both nuclear and electronic properties (including the elusive electronic momentum studied by Nafie). Moreover, only the latter (as opposed to the former) conserves the total linear and angular momentum in general. 

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4. Nuclear damage in LMNA mutant iPSC-derived cardiomyocytes is associated with impaired lamin localization to the nuclear envelope

   https://doi.org/10.1091/mbc.E21-10-0527  

   Wallace, Melanie; Zahr, Hind; Perati, Shriya; Morsink, Chloé D; Johnson, Lindsey E; Gacita, Anthony M; Lai, Shuping; Wallrath, Lori L; Benjamin, Ivor J; McNally, Elizabeth M; et al (November 2023, Molecular Biology of the Cell)

   Discher, Dennis (Ed.)

   The LMNA gene encodes the nuclear envelope proteins Lamins A and C, which comprise a major part of the nuclear lamina, provide mechanical support to the nucleus, and participate in diverse-intracellular signaling. LMNA mutations give rise to a collection of diseases called laminopathies, including dilated cardiomyopathy ( LMNA-DCM) and muscular dystrophies. Although nuclear deformities are a hallmark of LMNA-DCM, the role of nuclear abnormalities in the pathogenesis of -DCM remains incompletely understood. Using induced-pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LMNA-mutant patients and healthy controls, we show that LMNA mutant iPSC-CM nuclei have altered shape or increased size compared with healthy control iPSC-CM nuclei. The LMNA mutation exhibiting the most severe nuclear deformities, R249Q, additionally caused reduced nuclear stiffness and increased nuclear fragility. Importantly, for all cell lines, the degree of nuclear abnormalities corresponded to the degree of Lamin A/C and Lamin B1 mislocalization from the nuclear envelope. The mislocalization was likely due to altered assembly of Lamin A/C. Collectively, these results point to the importance of correct lamin assembly at the nuclear envelope in providing mechanical stability to the nucleus and suggests that defects in nuclear lamina organization may contribute to the nuclear and cellular dysfunction in LMNA-DCM. 

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5. A nuclear import pathway exploited by pathogenic noncoding RNAs

   https://doi.org/10.1093/plcell/koac210  

   Ma, Junfei; Dissanayaka Mudiyanselage, Shachinthaka D.; Park, Woong June; Wang, Mo; Takeda, Ryuta; Liu, Bin; Wang, Ying (July 2022, The Plant Cell)

   Abstract The prevailing view of intracellular RNA trafficking in eukaryotic cells is that RNAs transcribed in the nucleus either stay in the nucleus or cross the nuclear envelope, entering the cytoplasm for function. However, emerging evidence illustrates that numerous functional RNAs move in the reverse direction, from the cytoplasm to the nucleus. The mechanism underlying RNA nuclear import has not been well elucidated. Viroids are single-stranded circular noncoding RNAs that infect plants. Using Nicotiana benthamiana, tomato (Solanum lycopersicum), and nuclear-replicating viroids as a model, we showed that cellular IMPORTIN ALPHA-4 (IMPa-4) is likely involved in viroid RNA nuclear import, empirically supporting the involvement of Importin-based cellular pathway in RNA nuclear import. We also confirmed the involvement of a cellular protein (viroid RNA-binding protein 1 [VIRP1]) that binds both IMPa-4 and viroids. Moreover, a conserved C-loop in nuclear-replicating viroids serves as a key signal for nuclear import. Disrupting C-loop impairs VIRP1 binding, viroid nuclear accumulation, and infectivity. Further, C-loop exists in a subviral satellite noncoding RNA that relies on VIRP1 for nuclear import. These results advance our understanding of subviral RNA infection and the regulation of RNA nuclear import. 

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