# Biogenesis of macromolecular machines for post-transcriptional regulation of translation

> **NIH NIH R35** · EMORY UNIVERSITY · 2023 · $381,779

## Abstract

Summary:
Ribosomes are highly conserved RNA-protein complexes that direct protein synthesis in all cells. Dysregulation
of ribosome production or function is detrimental to gene expression and underlies several disease states. Over
2% of ribosomal RNA (rRNA) nucleotides are modified. These modifications play a critical role in the proper
production of ribosomes that can accurately perform protein synthesis. The two major rRNA modifications are
2’-O-methylation and pseudouridylation that are directed by highly conserved non-coding RNAs called small
nucleolar RNAs (snoRNAs). Altered levels of snoRNAs are associated with human diseases from
neurodegeneration to multiple types of cancer, underscoring their importance for proper cell growth. Therefore,
a key question is how levels of snoRNAs are regulated and how does their dysregulation lead to translation
defects in disease? Despite the textbook perception that rRNA modifications are equally deposited in all
ribosomes, recent advances in mapping modifications have revealed substoichiometric rRNA modification sites,
strongly suggesting that ribosome assembly and function may be regulated by the modification status of rRNA.
A long-term goal of my laboratory is to identify the post-transcriptional mechanisms that regulate the abundance
of snoRNAs and understand their contribution to cellular translational control. A prominent rRNA modification in
eukaryotes is 2’-O-methylation, the incorporation of which is guided by snoRNAs of the box C/D class. These
snoRNAs interact with a set of evolutionarily conserved proteins to form ribonucleoprotein complexes
(snoRNPs). The assembly of snoRNPs is highly regulated which, in turn, is important to maintain levels of
snoRNAs and to coordinate this process with other cellular events. However, despite their fundamental
importance, much of these regulatory events remains a black box. We have performed targeted yeast mutational
and suppressor screens of snoRNP assembly factors to determine their essential contributions and identify
genetic pathways that mediate snoRNP biogenesis. Our data indicate that regulation of box C/D snoRNP
production by assembly factors is critically important for control of the modification pattern of rRNAs and
dysregulation of this process alters the biogenesis pathway and the fidelity of ribosomes. Our goal is to combine
the novel genetic tools and reagents that we have recently developed with biochemical assays, structural biology,
proteomics, and next-generation sequencing to answer two key questions: 1) How do regulatory factors control
the steady-state levels of snoRNAs required for accurate modification of rRNA?; and 2) How do changes in
snoRNA levels alter and tune protein synthesis? These studies will provide significant insights into the control of
gene expression by snoRNAs at the translation level, and may inform our view of how snoRNA dysregulation
underlies human disease.

## Key facts

- **NIH application ID:** 10669201
- **Project number:** 5R35GM138123-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Homa Ghalei
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $381,779
- **Award type:** 5
- **Project period:** 2020-08-17 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10669201

## Citation

> US National Institutes of Health, RePORTER application 10669201, Biogenesis of macromolecular machines for post-transcriptional regulation of translation (5R35GM138123-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10669201. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*