Altered translation of GATA1 in Diamond-Blackfan anemia

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA)[superscript 1, 2], congenital asplenia[superscript 3] and T cell leukemia[superscript 4]. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type– and tissue-specific defects remains unknown[superscript 5]. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.National Institutes of Health (U.S.) (Grant P01 HL32262)National Institutes of Health (U.S.) (Grant U54 HG003067-09

Ribosomes

Ribosomes are fundamental components of the cell that are essential for its growth and proliferation. It is hard to imagine that such a fundamental physiological machinery, as ribosomes, does not participate in cancer biology. However, surprisingly, there is a lack of studies towards the role of ribosomal alterations in cancer. Here, we will attempt to summarize current knowledge regarding the link between the ribosomal machinery and human cancer. Various malfunctions in ribosomal activity represented by defects in ribosome biogenesis have been associated with human disease. Recent studies performed both in yeast and in higher eukaryotes have linked various aspects of ribosome biogenesis to the control of cell growth and proliferation. It is now clear that disruption of ribosome biogenesis is a cause of several inherited genetic disorders that have been associated with an increased risk of tumor development. In this chapter we discuss some recent insights into the mechanisms by which alterations in ribosome biogenesis contribute to the biology of cancer