# Regulation of the nucleolar RNA exosome in cancer

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $466,084

## Abstract

Project Summary
Deregulated over-activation of ribosome biogenesis and protein translation is tightly linked to human cancers.
Thus, ribosome biogenesis must be tightly regulated during normal cell homeostasis. Of many regulatory
accessory factors, the nucleolar RNA exosome plays a key role in ribosome biogenesis. It contains a 9-subunit
core and a distributive 3ʹ to 5ʹ exonuclease called hRrp6 (human EXOSC10) and mediates the processing and
degradation of nucleolar RNAs including pre-ribosomal RNA (rRNA) and snoRNAs. Currently it is largely
unknown how the RNA exosome is regulated in the nucleolus. We recently found that USP36, a nucleolar
deubiquitinating enzyme (Dub), binds to the exosome through direct interaction with hRrp6. Interestingly,
USP36 does not regulate the levels of hRrp6 and other exosome subunits. Instead, it acts as a novel SUMO
E3 and mediates SUMOylation of hRrp6 at Lys (K) 583 in cells and in vitro. Knockdown of either USP36 or
hRrp6 impairs rRNA processing and significantly inhibited cell proliferation. Intriguingly, mutating K583
impaired the binding of hRrp6 to pre-rRNAs and the K583R mutant failed to rescue the rRNA processing
defects caused by knockdown of endogenous hRrp6, indicating that hRrp6 SUMOylation is critical for hRrp6
binding to and the processing of pre-rRNA. These preliminary data lead to a novel hypothesis that USP36
regulates the nucleolar RNA exosome by acting as a novel SUMO E3, thus being critical for pre-rRNA
processing and ribosome biogenesis and implicated in cancer. To gain further insight into the role of USP36 in
regulating the nucleolar RNA exosome and ribosome biogenesis, we will investigate the molecular and
biochemical mechanisms underlying USP36 association with the nucleolar RNA exosome and the
SUMOylation of hRrp6 in Aim 1, including how USP36 interacts with the nucleolar RNA exosome, whether it
SUMOylates other exosome subunits and adaptor proteins, and how USP36 acts as a SUMO E3 for exosome
and its adaptor proteins. We will then focus on the functional role of USP36 regulation of RNA exosome in
ribosome biogenesis in Aim 2, including the investigation of the role of USP36-exosome regulation in ribosome
biogenesis, translation, nuclear RNA quality control as well as cell growth and proliferation. As USP36 is
frequently overexpressed in human cancers including breast cancers, we will elucidate whether USP36's
SUMO E3 activity contributes to tumorigenesis in Aim 3, including the investigation of if USP36 and its SUMO
E3 contribute to cell transformation in culture and mammary tumorigenesis in vivo using transgenic mouse
models, whether deletion of USP36 suppresses tumor formation and growth using knockout mouse models
and whether inhibiting USP36 suppresses breast cancer cell proliferation and this inhibition correlates with the
levels of SUMOylation. Achieving these goals will provide critical insight into how USP36 properly regulates the
RNA exosome SUMOylation in the nucleolus, how dere...

## Key facts

- **NIH application ID:** 10458409
- **Project number:** 1R01CA262104-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Mu-Shui Dai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $466,084
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458409

## Citation

> US National Institutes of Health, RePORTER application 10458409, Regulation of the nucleolar RNA exosome in cancer (1R01CA262104-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458409. Licensed CC0.

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