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1.
Elife ; 122023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37272618

RESUMO

Ribosomal protein (Rp) gene haploinsufficiency can result in Diamond-Blackfan Anemia (DBA), characterized by defective erythropoiesis and skeletal defects. Some mouse Rp mutations recapitulate DBA phenotypes, although others lack erythropoietic or skeletal defects. We generated a conditional knockout mouse to partially delete Rps12. Homozygous Rps12 deletion resulted in embryonic lethality. Mice inheriting the Rps12KO/+ genotype had growth and morphological defects, pancytopenia, and impaired erythropoiesis. A striking reduction in hematopoietic stem cells (HSCs) and progenitors in the bone marrow (BM) was associated with decreased ability to repopulate the blood system after competitive and non-competitive BM transplantation. Rps12KO/+ lost HSC quiescence, experienced ERK and MTOR activation, and increased global translation in HSC and progenitors. Post-natal heterozygous deletion of Rps12 in hematopoietic cells using Tal1-Cre-ERT also resulted in pancytopenia with decreased HSC numbers. However, post-natal Cre-ERT induction led to reduced translation in HSCs and progenitors, suggesting that this is the most direct consequence of Rps12 haploinsufficiency in hematopoietic cells. Thus, RpS12 has a strong requirement in HSC function, in addition to erythropoiesis.


Assuntos
Anemia de Diamond-Blackfan , Pancitopenia , Animais , Camundongos , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Eritropoese/genética , Genes Essenciais , Haploinsuficiência , Células-Tronco Hematopoéticas/metabolismo , Camundongos Knockout , Pancitopenia/genética , Pancitopenia/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
2.
Elife ; 112022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35179490

RESUMO

Ribosomal Protein (Rp) gene haploinsufficiency affects translation rate, can lead to protein aggregation, and causes cell elimination by competition with wild type cells in mosaic tissues. We find that the modest changes in ribosomal subunit levels observed were insufficient for these effects, which all depended on the AT-hook, bZip domain protein Xrp1. Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2α. eIF2α phosphorylation was itself sufficient to enable cell competition of otherwise wild type cells, but through Xrp1 expression, not as the downstream effector of Xrp1. Unexpectedly, many other defects reducing ribosome biogenesis or function (depletion of TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1α1, or eIF5A), also increased eIF2α phosphorylation and enabled cell competition. This was also through the Xrp1 expression that was induced in these depletions. In the absence of Xrp1, translation differences between cells were not themselves sufficient to trigger cell competition. Xrp1 is shown here to be a sequence-specific transcription factor that regulates transposable elements as well as single-copy genes. Thus, Xrp1 is the master regulator that triggers multiple consequences of ribosomal stresses and is the key instigator of cell competition.


Assuntos
Competição entre as Células , Proteínas de Drosophila , Animais , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fosforilação , Biossíntese de Proteínas , Ribossomos/metabolismo , Fatores de Transcrição/metabolismo
3.
Elife ; 102021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33847264

RESUMO

Aneuploidy causes birth defects and miscarriages, occurs in nearly all cancers and is a hallmark of aging. Individual aneuploid cells can be eliminated from developing tissues by unknown mechanisms. Cells with ribosomal protein (Rp) gene mutations are also eliminated, by cell competition with normal cells. Because Rp genes are spread across the genome, their copy number is a potential marker for aneuploidy. We found that elimination of imaginal disc cells with irradiation-induced genome damage often required cell competition genes. Segmentally aneuploid cells derived from targeted chromosome excisions were eliminated by the RpS12-Xrp1 cell competition pathway if they differed from neighboring cells in Rp gene dose, whereas cells with normal doses of the Rp and eIF2γ genes survived and differentiated adult tissues. Thus, cell competition, triggered by differences in Rp gene dose between cells, is a significant mechanism for the elimination of aneuploid somatic cells, likely to contribute to preventing cancer.


Aneuploid cells emerge when cellular division goes awry and a cell ends up with the wrong number of chromosomes, the tiny genetic structures carrying the instructions that control life's processes. Aneuploidy can lead to fatal conditions during development, and to cancer in an adult organism. A safety mechanism may exist that helps the body to detect and remove these cells. Yet, exactly this happens is still poorly understood: in particular, it is unclear how cells manage to 'count' their chromosomes. One way they could do so is through the ribosomes, the molecular 'factories' that create the building blocks required for life. In a cell, every chromosome carries genes that code for the proteins (known as Rps) forming ribosomes. Aneuploidy will alter the number of Rp genes, and in turn the amount and type of Rps the cell produces, so that ribosomes and the genes for Rps could act as a 'readout' of aneuploidy. Ji et al set out to test this theory in fruit flies. The first experiment used a genetic manipulation technique called site-specific recombination to remove parts of chromosomes from cells in the developing eye and wing. Cells which retained all their Rp genes survived, while those that were missing some usually died ­ but only when the surrounding cells were normal. In this situation, healthy cells eliminated their damaged neighbours through a process known as cell competition. A second experiment, using radiation as an alternative method of damaging chromosomes, also gave similar results. The work by Ji et al. reveals how the body can detect and eliminate aneuploid cells, potentially before they can cause harm. If the same mechanism applies in humans, boosting cell competition may, one day, helps to combat diseases like cancer.


Assuntos
Aneuploidia , Competição entre as Células , Drosophila melanogaster/fisiologia , Dosagem de Genes , Proteínas Ribossômicas/metabolismo , Animais , Drosophila melanogaster/crescimento & desenvolvimento , Humanos , Discos Imaginais/crescimento & desenvolvimento , Discos Imaginais/fisiologia , Neoplasias/genética
4.
PLoS Genet ; 15(12): e1008513, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31841522

RESUMO

Whereas complete loss of Rp function is generally lethal, most heterozygous Rp mutants grow more slowly and are subject to competitive loss from mosaics tissues that also contain wild type cells. The rpS12 gene has a special role in the cell competition of other Ribosomal Protein (Rp) mutant cells in Drosophila. Elimination by cell competition is promoted by higher RpS12 levels and prevented by a specific rpS12 mis-sense mutation, identifying RpS12 as a key effector of cell competition due to mutations in other Rp genes. Here we show that RpS12 is also required for other aspects of Rp mutant phenotypes, including hundreds of gene expression changes that occur in 'Minute' Rp heterozygous wing imaginal discs, overall translation rate, and the overall rate of organismal development, all through the bZip protein Xrp1 that is one of the RpS12-regulated genes. Our findings outline the regulatory response to mutations affecting essential Rp genes that controls overall translation, growth, and cell competition, and which may contribute to cancer and other diseases.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Discos Imaginais/crescimento & desenvolvimento , Biossíntese de Proteínas , Proteínas Ribossômicas/genética , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Discos Imaginais/metabolismo , Masculino , Mutação de Sentido Incorreto , Proteínas Ribossômicas/metabolismo , Análise de Sequência de RNA
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