# Regulation of  Ribosome Biogenesis in Hematopoietic Stem Cells

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $602,358

## Abstract

Abstract
Tightly-regulated protein synthesis rates are critical for hematopoietic stem cell (HSC) maintenance and function.
Mutations in ribosome proteins or genes that affect ribosome biogenesis cause “ribosomopathies”, a class of
bone marrow failure (BMF) syndromes. As prominently illustrated by Shwachman-Diamond Syndrome (SDS), a
BMF disease with progressive hematopoietic stem and progenitor cell (HSPC) failure and predisposition to
myeloid malignancies, is driven by germline biallelic mutations in the assembly factors essential for the
maturation of the 60S ribosome subunit. However, how ribosome assembly is regulated in HSCs remains poorly
understood, as is its contribution to hematopoietic dysfunction. Importantly, other than allogeneic stem cell
transplantation, therapeutic interventions that mitigate the HSPC defects in BMF do not exist. This application is
based on our new studies that uncovered a novel role for the E3 ubiquitin ligase, HectD1, in regulating HSC
function via ribosome biogenesis. Hectd1-deficient HSCs exhibit a striking defect in transplantation ability and
self-renewal, concomitant with a reduction in global protein synthesis. The mechanism underlying HSC
dysfunction upon Hectd1 deficiency is directly linked to aberrant ribosome assembly by ubiquitinating and
regulating the stability of ZNF622, a critical biogenesis factor for the maturation of the 60S large ribosomal
subunit in the cytoplasm. Depletion of HectD1 led to an accumulation of ZNF622 and the anti-association factor
eIF6 on the 60S subunit, decreased 80S monosome to 60S ratio, consistent with a subunit joining defect
associated with SDS-like diseases. Importantly, knockdown of ZNF622 in Hectd1-deficient cells restored protein
synthesis and HSC reconstitution capacity. This finding represents a rare in vivo example of genetic suppression
of HSC defects associated with dysfunctional ribosome biogenesis. The implications of this novel pathway to the
etiology of HSC failure and clinical treatment of “ribosomopathies”, mandates detailed mechanistic
understanding. Here, we propose comprehensive and in-depth analyses on the role of HectD1 and ZNF622 in
ribosome biogenesis and HSCs. In aim 1, we propose to investigate the roles of HectD1 and ZNF622 in HSCs
and how they interact to regulate HSC function, using a combination of complementary genetics, genomics, and
biochemical approaches. In aim 2, we will systematically analyze if HectD1/ZNF622 affects different aspects of
protein translation controls. Moreover, we will perform quantitative proteomics to assess if ribosome levels or
ribosome composition is affected by Hectd1/ZNF622 loss. In aim 3, we will interrogate potential dysregulation of
HECTD1 and ZNF622 in human BMF syndromes and explore therapeutic potential of targeting ZNF622 for the
treatment of BMF with dysfunctional ribosome biogenesis. Our study implicates a previously unappreciated role
of ubiquitination in regulating HSC function via controlling riboso...

## Key facts

- **NIH application ID:** 10143630
- **Project number:** 1R01DK127738-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Wei Tong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $602,358
- **Award type:** 1
- **Project period:** 2020-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143630

## Citation

> US National Institutes of Health, RePORTER application 10143630, Regulation of  Ribosome Biogenesis in Hematopoietic Stem Cells (1R01DK127738-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143630. Licensed CC0.

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