About

Onn Brandman is a professor whose research focuses on understanding the molecular and systems-level features of protein quality control and stress responses in health and disease. His work on Ribosome-associated Quality Control (RQC) has led to the discovery of a protein modification called a 'CAT tail,' which targets defective proteins for degradation. This discovery has created a new field of biology that is still developing. His lab also explores the systems biology of protein quality control, developing approaches for quantifying stress-response pathways in vivo, such as the ReporterSeq method, which measures transcriptional pathway induction under genome-wide CRISPR perturbations in diverse stress conditions. Additionally, his research includes the study of viscoadaptation, which investigates how cellular viscosity influences various pathways, including those related to protein quality control. Through exploring molecular mechanisms, systems-level features, and developing new technologies, Onn Brandman aims to advance understanding of cellular stress responses and protein quality control.

Research topics

• Cell biology
• Biology
• Chemistry
• Biochemistry
• Biophysics
• Physics
• Thermodynamics
• Biological system

Selected publications

• Nup42 safeguards heat-induced mRNAs from nuclear condensation to support chaperone synthesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-11

  articleOpen accessSenior authorCorresponding

  Cells exposed to acute stress selectively express stress-adaptive genes while repressing growth-related genes. Upon heat shock, most pre-existing mRNAs localize to translationally repressed biomolecular condensates. How heat-induced mRNAs evade condensation and remain translationally competent remains unclear. Here, we show that ribosomal protein-coding transcripts preferentially accumulate in condensates during heat shock, whereas heat-induced chaperone mRNAs are selectively excluded and preferentially translated. Using a whole-genome CRISPRi screening platform, Fractionation of Reporter-Seq (FRep-Seq), we identify the nucleoporin Nup42 as the strongest suppressor of heat-induced mRNA condensation. Loss of Nup42 triggers temperature- and transcription-dependent nuclear condensation of chaperone mRNAs, which are exported but remain translationally incompetent, leading to impaired chaperone production and thermosensitivity. Co-transcriptional mRNP packaging is a critical determinant of condensation in the absence of Nup42. Together, our findings reveal a nuclear, translation-independent layer of mRNP solubility control that enables heat shock gene expression.

  PublisherDOI

• CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice

  Science Translational Medicine · 2025-10-08 · 3 citations

  articleOpen access

  Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell–derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated ASCC3 variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the Fmr1 KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal Fmr1 KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive–like behavior, and social interaction deficits after 1 month in 2-month-old Fmr1 KO mice compared with untreated Fmr1 KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.

  PublisherOA PDFDOI

• Mechanical forces regulate the composition and fate of stalled nascent chains

  Molecular Cell · 2025-12-30 · 1 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Author response: Diffusive lensing as a mechanism of intracellular transport and compartmentalization

  2024-06-18

  peer-reviewOpen accessSenior author
  PublisherDOI

• Reviewer #1 (Public Review): Diffusive lensing as a mechanism of intracellular transport and compartmentalization

  2024-05-20

  peer-reviewOpen accessSenior author

  While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membraneless compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call "diffusive lensing," is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.

  PublisherDOI

• Diffusive lensing as a mechanism of intracellular transport and compartmentalization

  eLife · 2024-06-18 · 1 citations

  articleOpen accessSenior author

  While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects the movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membrane-less compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call ‘diffusive lensing,’ is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.

  PublisherDOI

• Mechanochemical forces regulate the composition and fate of stalled nascent chains

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-04 · 5 citations

  preprintOpen accessSenior authorCorresponding

  The ribosome-associated quality control (RQC) pathway resolves stalled ribosomes. As part of RQC, stalled nascent polypeptide chains (NCs) are appended with CArboxy-Terminal amino acids (CAT tails) in an mRNA-free, non-canonical elongation process. CAT tail composition includes Ala, Thr, and potentially other residues. The relationship between CAT tail composition and function has remained unknown. Using biochemical approaches in yeast, we discovered that mechanochemical forces on the NC regulate CAT tailing. We propose CAT tailing initially operates in an "extrusion mode" that increases NC lysine accessibility for on-ribosome ubiquitination. Thr in CAT tails enhances NC extrusion by preventing formation of polyalanine, which can form α-helices that lower extrusion efficiency and disrupt termination of CAT tailing. After NC ubiquitylation, pulling forces on the NC switch CAT tailing to an Ala-only "release mode" which facilitates nascent chain release from large ribosomal subunits and NC degradation. Failure to switch from extrusion to release mode leads to accumulation of NCs on large ribosomal subunits and proteotoxic aggregation of Thr-rich CAT tails.

  PublisherOA PDFDOI

• Author response: Diffusive lensing as a mechanism of intracellular transport and compartmentalization

  2024-05-20

  peer-reviewOpen accessSenior author

  While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membraneless compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call “diffusive lensing,” is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.

  PublisherDOI

• Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis

  Nature Communications · 2024-02-22 · 19 citations

  articleOpen access

  Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.

  PublisherOA PDFDOI

• Diffusive lensing as a mechanism of intracellular transport and compartmentalization

  eLife · 2024-05-20

  preprintOpen accessSenior author

  Abstract While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membraneless compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call “diffusive lensing,” is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.

  PublisherDOI

Recent grants

• Cellular regulation of viscosity

  NIH · $616k · 2023–2026

• Stress Response Pathways Regulating Protein Homeostasis

  NIH · $1.4M · 2024–2029

• mRNA Template-free Protein Elongation: a New Paradigm for Quality Control at the Ribosome

  NIH · $2.9M · 2015–2024

Frequent coauthors

• Jonathan S. Weissman

  Whitehead Institute for Biomedical Research

  58 shared

• Tobias Meyer

  Cornell University

  34 shared

• Achuthan Raja Venkatesh

  Stanford University

  24 shared

• Matthew H. Larson

  Illumina (United States)

  22 shared

• Kathy H. Le

  Stanford University

  21 shared

• David Weld

  21 shared

• Jennifer A. Doudna

  University of California, Berkeley

  20 shared

• Rajat Rohatgi

  Stanford University

  19 shared