Parissa Monem

All Publications

• eIF5A and polyamines restrict mRNA levels in response to ribosome stalls. Proceedings of the National Academy of Sciences of the United States of America Wohlenberg, C. M., Monem, P. C., Barbosa, N., Frydman, J., Arribere, J. A. 2026; 123 (37): e2533876123

  Abstract

  Obstacles to translation elongation stall ribosomes and allow deleterious proteins to accumulate, which threatens cellular health. Cells recognize and clear stalled ribosomes via several interrelated pathways, although the mechanisms by which cells distinguish stalled from normally elongating ribosomes and mount an appropriate response are incompletely understood. While recent work highlights how ribosome collisions help cells to recognize stalled ribosomes, how other factors contribute to detection remains unclear. Here, we report a requirement for the translational factor eIF5A in the mRNA decay response to ribosomal stalling, i.e., No-Go mRNA Decay (NGD). We identified the Caenorhabditis elegans polyamine transporter, catp-6, via a forward genetic screen as a factor required for NGD. During our mechanistic dissection of the catp-6 phenotype, we uncovered a role for cellular polyamines and the translation elongation factor eIF5A in NGD, and we show this requirement is conserved from C. elegans to Saccharomyces cerevisiae. Our analyses support the idea that cells use eIF5A to identify ribosomal stalls and execute NGD and uncover a molecular function for a core protein synthesis factor in limiting expression from stall-inducing mRNAs. Our work offers insight into how cells identify and remove problematic mRNAs from the translational pool. Our work also raises the possibility that dysregulated mRNA decay is an unrecognized pathophysiology associated with polyaminopathies and eIF5A disorders, of relevance to varied neurodegenerative and aging phenotypes and efforts to pharmacologically inhibit eIF5A.

  View details for DOI 10.1073/pnas.2533876123

  View details for PubMedID 42709785

• A ubiquitin language communicates ribosomal distress. Seminars in cell & developmental biology Monem, P. C., Arribere, J. A. 2024; 154 (Pt B): 131-137

  Abstract

  Cells entrust ribosomes with the critical task of identifying problematic mRNAs and facilitating their degradation. Ribosomes must communicate when they encounter and stall on an aberrant mRNA, lest they expose the cell to toxic and disease-causing proteins, or they jeopardize ribosome homeostasis and cellular translation. In recent years, ribosomal ubiquitination has emerged as a central signaling step in this process, and proteomic studies across labs and experimental systems show a myriad of ubiquitination sites throughout the ribosome. Work from many labs zeroed in on ubiquitination in one region of the small ribosomal subunit as being functionally significant, with the balance and exact ubiquitination sites determined by stall type, E3 ubiquitin ligases, and deubiquitinases. This review discusses the current literature surrounding ribosomal ubiquitination during translational stress and considers its role in committing translational complexes to decay.

  View details for DOI 10.1016/j.semcdb.2023.03.009

  View details for PubMedID 36963992

  View details for PubMedCentralID PMC10878831

• Ubiquitination of stalled ribosomes enables mRNA decay via HBS-1 and NONU-1 in vivo. PLoS genetics Monem, P. C., Vidyasagar, N., Piatt, A. L., Sehgal, E., Arribere, J. A. 2023; 19 (1): e1010577

  Abstract

  As ribosomes translate the genetic code, they can encounter a variety of obstacles that hinder their progress. If ribosomes stall for prolonged times, cells suffer due to the loss of translating ribosomes and the accumulation of aberrant protein products. Thus to protect cells, stalled ribosomes experience a series of reactions to relieve the stall and degrade the offending mRNA, a process known as No-Go mRNA Decay (NGD). While much of the machinery for NGD is known, the precise ordering of events and factors along this pathway has not been tested. Here, we deploy C. elegans to unravel the coordinated events comprising NGD. Utilizing a novel reporter and forward and reverse genetics, we identify the machinery required for NGD. Our subsequent molecular analyses define a functional requirement for ubiquitination on at least two ribosomal proteins (eS10 and uS10), and we show that ribosomes lacking ubiquitination sites on eS10 and uS10 fail to perform NGD in vivo. We show that the nuclease NONU-1 acts after the ubiquitin ligase ZNF-598, and discover a novel requirement for the ribosome rescue factors HBS-1/PELO-1 in mRNA decay via NONU-1. Taken together, our work demonstrates mechanisms by which ribosomes signal to effectors of mRNA repression, and we delineate links between repressive factors working toward a well-defined NGD pathway.

  View details for DOI 10.1371/journal.pgen.1010577

  View details for PubMedID 36626369

  View details for PubMedCentralID PMC9870110

• NONU-1 Encodes a Conserved Endonuclease Required for mRNA Translation Surveillance. Cell reports Glover, M. L., Burroughs, A. M., Monem, P. C., Egelhofer, T. A., Pule, M. N., Aravind, L., Arribere, J. A. 2020; 30 (13): 4321-4331.e4

  Abstract

  Cellular translation surveillance rescues ribosomes that stall on problematic mRNAs. During translation surveillance, endonucleolytic cleavage of the problematic mRNA is a critical step in rescuing stalled ribosomes. Here we identify NONU-1 as a factor required for translation surveillance pathways including no-go and nonstop mRNA decay. We show that (1) NONU-1 reduces nonstop and no-go mRNA levels; (2) NONU-1 contains an Smr RNase domain required for mRNA decay; (3) the domain architecture and catalytic residues of NONU-1 are conserved throughout metazoans and eukaryotes, respectively; and (4) NONU-1 is required for the formation of mRNA cleavage fragments in the vicinity of stalled ribosomes. We extend our results in C. elegans to homologous factors in S. cerevisiae, showing the evolutionarily conserved function of NONU-1. Our work establishes the identity of a factor critical to translation surveillance and will inform mechanistic studies at the intersection of translation and mRNA decay.

  View details for DOI 10.1016/j.celrep.2020.03.023

  View details for PubMedID 32234470

  View details for PubMedCentralID PMC7184879