Ribosomal protein deficiencies linked to DiamondBlackfan anemia induce distinctive alterations of ATF4 expression

被引：0
作者：
Lorenzo-Martin, L. Francisco [1 ,2 ]
Robles-Valero, Javier [1 ,2 ,3 ]
Ramirez-Cota, Rosa [1 ,2 ]
Gaspar, Sonia G. [1 ,2 ]
Fuentes, Pedro [4 ]
Gentilella, Antonio [4 ,5 ]
Bustelo, Xose R. [1 ,2 ,3 ]
Dosil, Mercedes [1 ,2 ,3 ,6 ]
机构：
[1] CSIC Univ Salamanca, Ctr Invest Canc, Campus Unamuno, Salamanca 37007, Spain
[2] CSIC Univ Salamanca, Inst Biol Mol & Celular Canc, Campus Unamuno, Salamanca 37007, Spain
[3] CSIC Univ Salamanca, Ctr Invest Biomed Red Canc CIBERONC, Campus Unamuno, Salamanca 37007, Spain
[4] Bellvitge Biomed Res Inst IDIBELL, Lab Canc Metab, ONCOBELL Program, Barcelona, Spain
[5] Univ Barcelona, Fac Pharm & Food Sci, Dept Biochem & Physiol, Barcelona, Spain
[6] Univ Salamanca, Dept Bioquim & Biol Mol, Campus Unamuno, Salamanca 37007, Spain
来源：
ISCIENCE | 2025年 / 28卷 / 04期
关键词：
DIAMOND-BLACKFAN ANEMIA; BONE-MARROW FAILURE; ERYTHROPOIESIS FAILURE; GENE-EXPRESSION; BIOGENESIS; STRESS; TRANSLATION; CANCER; REINITIATION; PATHWAY;
D O I：
10.1016/j.isci.2025.112138
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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.
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页数：24
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