# Ribosomal protein deficiencies linked to Diamond-Blackfan anemia induce distinctive alterations of ATF4 expression

## TL;DR

This study shows that ribosomal protein deficiencies in Diamond-Blackfan anemia reduce ATF4 levels, worsening anemia and causing fetal hemoglobin de-repression.

## Contribution

The study identifies a p53-independent mechanism linking ribosomal protein deficiencies to ATF4 downregulation in Diamond-Blackfan anemia.

## Key findings

- ATF4 expression is reduced more severely in 40S than in 60S subunit deficiencies.
- ATF4 downregulation correlates with the severity of erythroid differentiation defects in DBA patients.
- Ribosome biogenesis defects cause de-repression of fetal hemoglobin in erythroid cells.

## Abstract

Ribosomal protein haploinsufficiency causes Diamond-Blackfan anemia (DBA) and other ribosomopathies. DBA has been linked to p53 activation and reduced GATA1 expression, but these mechanisms do not fully explain the disease. This study unveils that deficiencies in small (RPS) or large (RPL) ribosomal subunit proteins cause a p53-independent loss of ATF4, a master regulator of stress responses and erythropoiesis, by reducing the pool of actively translating ATF4 mRNAs. This defect is more pronounced in RPS deficiencies because the loss of 40S, but not 60S, subunits cause a destabilization of ATF4 transcripts. ATF4 downregulation occurs in early hematopoietic progenitors and correlates with the severity of erythroid differentiation defects in patients with DBA. It is also linked to the de-repression of fetal hemoglobin in erythroid cells, a frequent feature in patients with DBA. Our findings indicate that impaired ATF4 expression might be a primary contributor to DBA and explain the aggravated erythroid failure of RPS-mutant patients.

•ATF4 mRNA levels and translation are highly dependent on ribosome subunit production•ATF4 expression is reduced more severely in 40S than in 60S subunit deficiencies•ATF4 function is compromised in patients with DBA with strong erythropoiesis defects•Ribosome biogenesis defects induce the de-repression of fetal globin expression

ATF4 mRNA levels and translation are highly dependent on ribosome subunit production

ATF4 expression is reduced more severely in 40S than in 60S subunit deficiencies

ATF4 function is compromised in patients with DBA with strong erythropoiesis defects

Ribosome biogenesis defects induce the de-repression of fetal globin expression

Biochemistry; Molecular biology; Omics