Biology subjects

Neurohr, G. E.

Publications and source records attributed to Neurohr, G. E..

6 recordsLinked to original sources

bioRxiv2026

Rewired mRNA homeostasis enforces cell-size associated senescence

Cellular senescence refers to a permanent state of cell cycle exit and plays a key role in blocking the proliferation of compromised cells. Despite diverse drivers, senescent cells often share common features, one of which is their increased size. Though previously viewed as a passive outcome of cell growth during senescence, recent work shows that excess cell size can actively promote senescence via the p53-p21 pathway, making it both a consequence and a cause of cell cycle arrest. How cells sense their own size and communicate this information to the cell cycle control apparatus remains unresolved. Using genome-wide proximity mapping, we show that excess cell size globally redistributes chromatin between nuclear speckles and the nuclear lamina. These changes correspond with altered gene expression profiles, including the de-repression of typically silenced lamina-associated genes, some of which are involved in the senescence-associated secretory phenotype (SASP). Consistent with altered nuclear speckle function, we find that excess cell size perturbs normal splice isoform usage. In particular, MDM4, a negative regulator of p53 signaling, is differentially spliced when cells become enlarged to yield a non-functional variant, MDM4-S. Re-introducing correctly spliced MDM4 transcripts restores G1 cell cycle progression, thereby reverting senescent phenotypes in enlarged cells. Together, these data indicate that excess cell size is sensed via changes in mRNA homeostasis associated with a reorganized genome, driving both the secretory phenotype and permanent cell cycle exit that are characteristic of cellular senescence.

cell biology↗

bioRxiv2026

Protein-driven colloid-osmotic pressure controls nuclear size, organization, and function

The size of the cell nucleus is tightly controlled and changes in nuclear size correlate with altered nuclear function during development, cell differentiation and senescence. How nuclear size is regulated and whether changes thereof are functionally relevant remains unclear. Here, we demonstrate that nuclear size is determined by the osmotic pressure exerted by proteins in yeast, human cells and frog egg extracts. The biophysical model we establish solves the long-standing question of how the nuclear-to-cytoplasmic ratio is regulated and maintained. Furthermore, altering protein-driven osmotic balance modulates the physical properties of the nucleus, with a direct effect on chromatin organization and gene expression: Nuclear enlargement causes the dissolution of heterochromatic structures and derepression of subtelomeres and transposons, while simultaneously down-regulating highly expressed housekeeping genes. Importantly, these global transcriptional patterns closely mimic the gene expression changes that occur as yeast, human, and drosophila cells enlarge. Importantly, artificially forcing nuclear compression is sufficient to reverse these size-associated expression changes. Together, our findings provide a quantitative, mechanistic explanation for the coupling between the size of the nucleus and the cell, and they establish nuclear size as a modulator of chromatin organization and gene expression.

cell biology↗

bioRxiv2026

Weak interactions drive selective proteome demixing and tune the differential response to environmental perturbations

The intracellular space is a crowded environment where macromolecules perform distinct tasks despite pervasive "non-specific" interactions. Whether these interactions are functionally relevant and how they influence cellular organization remains unclear. Here, we developed QuPID-MS, which measures the propensity of proteins to phase separate in native cell extracts proteome-wide. We find that weak interactions drive condensation of half of the proteome in a crowding- and temperature-dependent manner and we present evidence that this proteome demixing occurs in cells. Importantly, protein condensation properties are conserved and broadly change when cells adapt to new environments, demonstrating that weak interactions are regulated and linked to function. Indeed, condensation of the growth regulator TORC1 coincides with its rapid inactivation, while high solubility of the stress-activated Hog1 ensures its activity across conditions. We thus uncover a fundamental organizing principle that allows tuning of cell growth to environmental fluctuations while ensuring other processes function robustly despite perturbations.

cell biology↗

bioRxiv2026

Non-coding DNA dictates cell size and impairs fitness by sequestering RNA polymerase

Genome size varies greatly between organisms, largely because of varying amounts of non-coding DNA. In multicellular organisms, non-coding DNA can make up 99% of the genome, while unicellular organisms have little non-coding information. How non-coding DNA affects cell physiology remains a key question in understanding genome evolution. Here, we developed a system to conditionally accumulate large amounts of non-coding DNA in budding yeast cells. We show that cells adjust their size to DNA content, regardless of its coding capacity. The direct coupling of cell size to DNA content occurs independently of the known cell size control and DNA damage checkpoints and explains the long-observed correlation between cell size, genome size, and ploidy. Furthermore, we find that excess non-functional DNA compromises cell fitness and renders them hypersensitive to transcription inhibitors. Providing a potential explanation for this observation, we uncover that the transcription machinery binds non-coding DNA and is titrated away from coding genes, resulting in a reduced overall concentration of yeast transcripts. We propose that the inability of yeast to repress non-coding DNA increases the fitness cost associated with non-functional DNA and prevents its expansion in the yeast genome on evolutionary timescales.

cell biology↗

bioRxiv2022

Cell cycle progression defects and impaired DNA damage signaling drive enlarged cells into senescence

Cellular senescence plays an important role in development, ageing, and cancer biology. Senescence is associated with increased cell size, but how this contributes to permanent cell cycle exit is poorly understood. Using reversible G1 cell cycle arrests combined with growth rate modulation, we examined the effects of excess cell size on cell cycle progression in human cells. We show that enlarged cells paradoxically have high levels of G1/S regulators relative to cells that were maintained at physiological size but also induce p21, which restrains cell cycle entry and protects against cell division failure. Furthermore, we find that enlarged cells bear an increased propensity for DNA breakage and concomitant DNA damage repair defects that are established during G1. Based on these observations, we propose that impaired DNA damage repair pathways prime enlarged cells for persistent replication-acquired damage, ultimately leading to catastrophic cell cycle failure and permanent cell cycle exit.

cell biology↗

bioRxiv2021

The environmental stress response regulates ribosome content in cell cycle-arrested S. cerevisiae

Temperature sensitive cell division cycle (cdc-ts) cells are unable to progress through the cell cycle at the restrictive temperature due to mutations in genes essential to cell cycle progress. Cells harboring cdc-ts mutations increase in cell volume upon arrest but eventually stop growing. We found that this attenuation in growth was due to selective downregulation of ribosome concentration. We saw similar ribosome downregulation in cells arrested in the cell cycle through alpha factor addition, rapamycin addition, and entrance into stationary phase. In all cell cycle arrests studied, cells activated the Environmental Stress Response (ESR), a key transcriptional response to many stressors in S. cerevisiae. When we combined cell cycle arrest with hyperactivation of the Ras/PKA pathway, ESR activation was prevented, cells were unable to downregulate their ribosomes, and cell viability was decreased. Our work uncovers a key role for the environmental stress response in coupling cell cycle progression to biomass accumulation.

cell biology↗