Shwachman-Diamond Syndrome and the Quality Control of Ribosome Assembly

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-42-SCI-42
Author(s):  
Alan J. Warren
Keyword(s):  
Quality Control ◽  
Ribosomal Proteins ◽  
Active Sites ◽  
Structural Integrity ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
Ribosome Assembly ◽  
Final Maturation ◽  
Shwachman Diamond Syndrome

Abstract The synthesis of new ribosomes is a fundamental conserved process in all cells. Ribosomes are pre-assembled in the nucleus and subsequently exported to the cytoplasm where they acquire functionality through a series of final maturation steps that include formation of the catalytic center, recruitment of the last remaining ribosomal proteins and the removal of inhibitory assembly factors. Surprisingly, a number of key factors (SBDS, DNAJC21, RPL10 (uL16)) involved in late cytoplasmic maturation of the large (60S) ribosomal subunit are mutated in both inherited and sporadic forms of leukemia. In particular, biallelic mutations in the SBDS gene cause Shwachman-Diamond syndrome (SDS), a recessive bone marrow failure disorder with significant predisposition to acute myeloid leukemia. By using the latest advances in single-particle cryo-electron microscopy to elucidate the function of the SBDS protein, we have uncovered an elegant mechanism that couples final maturation of the 60S subunit to a quality control assessment of the structural integrity of the active sites of the ribosome. Further molecular dissection of this pathway may inform novel therapeutic strategies for SDS and leukemia more generally. References: 1. Weis F, Giudice E, Churcher M,et al. Mechanism of eIF6 release from the nascent 60S ribosomal subunit. Nat Struct Mol Biol, (2015) Nov;22(11):914-9. 2. Wong CC, Traynor D, Basse N, et al. Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper, Blood. 2011 Oct 20;118(16):4305-12. 3. Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev (2011) 25: 917-929. 4. Menne TM, Goyenechea B, Sánchez-Puig N, et al. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95. Disclosures No relevant conflicts of interest to declare.

scholarly journals The modifying enzyme Tsr3 establishes the hierarchy of Rio kinase activity in 40S ribosome assembly

2021 ◽  
Author(s):  
Haina Huang ◽  
Melissa Parker ◽  
Katrin Karbstein
Keyword(s):  
Quality Control ◽  
Binding Site ◽  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
Kinase Activity ◽  
Ribosomal Subunit ◽  
Ribosome Assembly ◽  
Small Ribosomal Subunit ◽  
Yeast Strains

AbstractRibosome assembly is an intricate process, which in eukaryotes is promoted by a large machinery comprised of over 200 assembly factors (AF) that enable the modification, folding, and processing of the ribosomal RNA (rRNA) and the binding of the 79 ribosomal proteins. While some early assembly steps occur via parallel pathways, the process overall is highly hierarchical, which allows for the integration of maturation steps with quality control processes that ensure only fully and correctly assembled subunits are released into the translating pool. How exactly this hierarchy is established, in particular given that there are many instances of RNA substrate “handover” from one highly related AF to another remains to be determined. Here we have investigated the role of Tsr3, which installs a universally conserved modification in the P-site of the small ribosomal subunit late in assembly. Our data demonstrate that Tsr3 separates the activities of the Rio kinases, Rio2 and Rio1, with whom it shares a binding site. By binding after Rio2 dissociation, Tsr3 prevents rebinding of Rio2, promoting forward assembly. After rRNA modification is complete, Tsr3 dissociates, thereby allowing for recruitment of Rio1. Inactive Tsr3 blocks Rio1, which can be rescued using mutants that bypass the requirement for Rio1 activity. Finally, yeast strains lacking Tsr3 randomize the binding of the two kinases, leading to the release of immature ribosomes into the translating pool. These data demonstrate a role for Tsr3 and its modification activity in establishing a hierarchy for the function of the Rio kinases.

scholarly journals The modifying enzyme Tsr3 establishes the hierarchy of Rio kinase activity in 40S ribosome assembly

RNA ◽  
2022 ◽  
pp. rna.078994.121
Author(s):  
Haina Huang ◽  
Melissa D Parker ◽  
Katrin Karbstein
Keyword(s):  
Quality Control ◽  
Binding Site ◽  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
Kinase Activity ◽  
Ribosomal Subunit ◽  
Ribosome Assembly ◽  
Small Ribosomal Subunit ◽  
Yeast Strains

Ribosome assembly is an intricate process, which in eukaryotes is promoted by a large machinery comprised of over 200 assembly factors (AF) that enable the modification, folding, and processing of the ribosomal RNA (rRNA) and the binding of the 79 ribosomal proteins. While some early assembly steps occur via parallel pathways, the process overall is highly hierarchical, which allows for the integration of maturation steps with quality control processes that ensure only fully and correctly assembled subunits are released into the translating pool. How exactly this hierarchy is established, in particular given that there are many instances of RNA substrate “handover” from one highly related AF to another remains to be determined. Here we have investigated the role of Tsr3, which installs a universally conserved modification in the P-site of the small ribosomal subunit late in assembly. Our data demonstrate that Tsr3 separates the activities of the Rio kinases, Rio2 and Rio1, with whom it shares a binding site. By binding after Rio2 dissociation, Tsr3 prevents rebinding of Rio2, promoting forward assembly. After rRNA modification is complete, Tsr3 dissociates, thereby allowing for recruitment of Rio1. Inactive Tsr3 blocks Rio1, which can be rescued using mutants that bypass the requirement for Rio1 activity. Finally, yeast strains lacking Tsr3 randomize the binding of the two kinases, leading to the release of immature ribosomes into the translating pool. These data demonstrate a role for Tsr3 and its modification activity in establishing a hierarchy for the function of the Rio kinases.

Impaired Ribosome Maturation In Human Cells Depleted of Shwachman-Diamond Syndrome Protein SBDS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2242-2242
Author(s):  
Gulay Sezgin ◽  
Abdallah Nihrane ◽  
Adrianna Henson ◽  
Max Wattenberg ◽  
Steven Ellis ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
A549 Cells ◽  
Autosomal Recessive Disorder ◽  
Human Cells ◽  
Yeast Cells ◽  
Cycle Phase ◽  
Shwachman Diamond Syndrome ◽  
Pancreatic Exocrine Dysfunction

Abstract Abstract 2242 Background: Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine dysfunction, neurocognitive and skeletal abnormalities, and bone marrow failure. Mutations in SBDS have been shown to cause SDS. From experiments on its yeast ortholog (Haematologica 2010. 95:57-64), SBDS has been implicated in maturation and function of the 60S ribosomal subunit. In particular, subunit maturation in the SDS yeast model was associated with delayed export and accumulation of 60S-like particles in the nucleoplasm. Methods and Results: To clarify its role in human cells, erythroleukemia TF-1 cells were transduced with lentiviral vectors expressing short hairpin RNA (shRNA) against SBDS. Immunoblot assays confirmed approximately 60% knockdown in individual TF-1 cell clones expressing different shRNAs. The growth and hematopoietic colony forming potential of TF-1 knockdown cells were markedly hindered when compared to cells stably transduced with shRNA against a scrambled SBDS sequence. Using Hoechst 33342/Pyronin Y staining and flow cytometry, we also found an increased percentage of knockdown cells retained at the G0/G1 cell cycle phase. To address whether near-complete knockdown of SBDS affected ribosome synthesis as it does in yeast cells, we silenced SBDS in A549 cells. Our data revealed a reduction in polysomes but in contrast to what was observed in yeast, there was no evidence of half-mer polysomes indicative of decreased 60S subunits participating in translation. The absence of half-mers is not unusual in mammalian systems, so to better analyze the effect of SBDS on 60S subunit maturation subunit localization was assessed by co-transfection with a vector expressing a fusion between human RPL29 and enhanced GFP. Preliminary studies indicated a higher percentage of SBDS-depleted cells with nuclear localization of 60S subunits, when compared with normal controls (Fig. 1). Conclusions: Disclosures: No relevant conflicts of interest to declare.

Linking Defective Ribosome Maturation to Shwachman-Diamond Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-36-SCI-36
Author(s):  
Alan John Warren
Keyword(s):  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Ribosomal Subunit ◽  
Protein Translation ◽  
Ribosome Assembly ◽  
Genetic Dissection ◽  
Gtp Hydrolysis ◽  
Shwachman Diamond Syndrome ◽  
Novel Therapeutic Strategies ◽  
Syndrome Protein

Abstract Ribosomes are RNA-protein machines that translate the genetic information encoded by the mRNA template in all living cells. Recent high-resolution structures of the ribosome have revolutionized our understanding of protein translation. However, the mechanisms of ribosome assembly and the surveillance mechanisms that monitor this process and couple it to growth are poorly understood. Causative mutations and deletions of genes involved in ribosome biogenesis define an emerging group of disorders known as the ribosomopathies. Recent work from my laboratory strongly supports the hypothesis that Shwachman-Diamond syndrome (SDS) is a ribosomopathy caused by defective maturation of the large ribosomal subunit. Elucidation of the specific function of the SBDS protein that is deficient in SDS is revealing unexpected new insights that extend our understanding of the mechanisms underlying the late cytoplasmic steps of ribosome assembly and the quality control surveillance pathways that monitor 60S maturation. Genetic dissection of this pathway may inform novel therapeutic strategies for SDS. 1. Wong C.C., Traynor D., Basse N., Kay R.R., Warren A.J. Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper, Blood. 2011 Oct 20;118(16):4305-12. 2. Finch A.J., Hilcenko C., Basse N., Drynan L.F., Goyenechea B., Menne T.F., González Fernández Á., Simpson P., D’Santos C.S., Arends M.J., Donadieu J., Bellanné-Chantelot C., Costanzo M., Boone C., McKenzie A.N., Freund S.M., Warren A.J. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes and Development (2011) 25: 917-929. 3. Menne T.M., Goyenechea B., Sánchez-Puig N., Wong C.C., Tonkin L.M., Ancliff P., Brost R.L., Costanzo M., Boone C. and Warren A.J. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Defective ribosome assembly in Shwachman-Diamond syndrome

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4305-4312 ◽  
Author(s):  
Chi C. Wong ◽  
David Traynor ◽  
Nicolas Basse ◽  
Robert R. Kay ◽  
Alan J. Warren
Keyword(s):  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Pancreatic Insufficiency ◽  
Ribosomal Subunit ◽  
Initiation Factor ◽  
Ribosome Assembly ◽  
Restrictive Temperature ◽  
Poor Growth ◽  
Shwachman Diamond Syndrome ◽  
Subunit Joining

AbstractShwachman-Diamond syndrome (SDS), a recessive leukemia predisposition disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, skeletal abnormalities and poor growth, is caused by mutations in the highly conserved SBDS gene. Here, we test the hypothesis that defective ribosome biogenesis underlies the pathogenesis of SDS. We create conditional mutants in the essential SBDS ortholog of the ancient eukaryote Dictyostelium discoideum using temperature-sensitive, self-splicing inteins, showing that mutant cells fail to grow at the restrictive temperature because ribosomal subunit joining is markedly impaired. Remarkably, wild type human SBDS complements the growth and ribosome assembly defects in mutant Dictyostelium cells, but disease-associated human SBDS variants are defective. SBDS directly interacts with the GTPase elongation factor-like 1 (EFL1) on nascent 60S subunits in vivo and together they catalyze eviction of the ribosome antiassociation factor eukaryotic initiation factor 6 (eIF6), a prerequisite for the translational activation of ribosomes. Importantly, lymphoblasts from SDS patients harbor a striking defect in ribosomal subunit joining whose magnitude is inversely proportional to the level of SBDS protein. These findings in Dictyostelium and SDS patient cells provide compelling support for the hypothesis that SDS is a ribosomopathy caused by corruption of an essential cytoplasmic step in 60S subunit maturation.

scholarly journals Cryo-EM structure of a late pre-40S ribosomal subunit from Saccharomyces cerevisiae

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
André Heuer ◽  
Emma Thomson ◽  
Christian Schmidt ◽  
Otto Berninghausen ◽  
Thomas Becker ◽  
...  
Keyword(s):  
Active Sites ◽  
18S Rrna ◽  
Structural Integrity ◽  
Ribosomal Subunit ◽  
Structural Knowledge ◽  
40S Ribosomal Subunit ◽  
Final Maturation ◽  
Assembly Factors ◽  
Mrna Binding ◽  
Ribosome Formation

Mechanistic understanding of eukaryotic ribosome formation requires a detailed structural knowledge of the numerous assembly intermediates, generated along a complex pathway. Here, we present the structure of a late pre-40S particle at 3.6 Å resolution, revealing in molecular detail how assembly factors regulate the timely folding of pre-18S rRNA. The structure shows that, rather than sterically blocking 40S translational active sites, the associated assembly factors Tsr1, Enp1, Rio2 and Pno1 collectively preclude their final maturation, thereby preventing untimely tRNA and mRNA binding and error prone translation. Moreover, the structure explains how Pno1 coordinates the 3’end cleavage of the 18S rRNA by Nob1 and how the late factor’s removal in the cytoplasm ensures the structural integrity of the maturing 40S subunit.

scholarly journals Expression of Human SBDSR126T in Sbds Null Background Shows Eif6 Dysregulation: An Adult Zebrafish Model for Shwachman-Diamond Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3737-3737
Author(s):  
Usua Oyarbide Cuervas-Mons ◽  
Matthew Snyderman ◽  
Jacek Topczewski ◽  
Seth J. Corey
Keyword(s):  
Transgenic Line ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
Zebrafish Model ◽  
80S Ribosome ◽  
Early Juvenile Stage ◽  
Increased Risk ◽  
Skeletal Defects ◽  
Shwachman Diamond Syndrome

Background. Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic insufficiency, skeletal defects, neutropenia, and an increased risk of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). SDS occurs in 1/75,000 births, and biallelic mutations in the SBDS gene account for ~90% of patients. The SBDS protein is highly conserved. SBDS interacts physically with EFL1 to release EIF6 from the cytoplasmic pre-60S ribosomal subunit and promote the assembly of the mature 80S ribosome. The SBDS R126T allele is found in combination with the common K62X mutation in some SDS patient. A recent study showed that the SBDSR126T is not able to activate the GTPase activity of the EFL1, affecting the release of EIF6 from the 60S surface. Methods. We created a zebrafish knockout line that phenocopies the SDS with neutropenia, pancreas atrophy, small size (Figure 1A), and decreased 80S ribosomes. To rescue those fish from early mortality, we generated a new transgenic line Tg(ubi:SBDSR126T:pA) expressing the missense variant R126T, a disease-associated allele. Results. The sbds knockout fish die after 21 days post fertilization (dpf), corresponding to an early juvenile stage. However, the SBDSR126T transgenic line in the background of the sbds knockout can live for at least 12 months. This is in strong contrast to the mouse SbdsR126T/R126T line that do not survive to birth. Transgenically-rescued fish displayed a small size phenotype resembling SDS (Figure 1B). Levels of ribosomal proteins Rpl5 and Rpl11 were lower in the sbds knockout at 21 dpf but they were normal in the transgenic line at 6 months. We also observed a concordant regulation of Sbds and Eif6 expression (Figure 1C,D). sbds null fish showed a significant upregulation of cdkn1a, while in their transgenic siblings levels were normal (Figure 1E). Moreover, mpx was upregulated in the transgenic line with the null background (Figure 1F). Analysis of neutrophil and monocyte counts are being performed and will be reported. Conclusions. Our novel SBDSR126T zebrafish model survives until adulthood, which will allow us to carry out a number of informative assays such as stress response, gene expression, and polysome profiles in different organs. Rpl5 and Rpl11 levels are affected in sbds mutants but not in the transgenic line. Activation of cdkn1a (p21) in sbds mutants might lead to apoptosis and death. The normal levels of cdkn1a in the transgenic line might be non-deleterious, as loss of Tp53 activation can rescue some models of bone marrow failure. In addition, loss of sbds or expression of SBDSR126T affect Eif6 levels in zebrafish. Importantly, some patients with SBDS deficiency acquire interstitial deletions of chromosome 20, resulting in the loss of the EIF6 gene. This might be a potential mechanism to suppress the defect in ribosome biogenesis by reducing the copy number of the EIF6 gene and has been related to a lower risk of MDS/AML comparing to other SDS patients. Our adult model of Shwachman-Diamond Syndrome can provide new insights into the pathogenesis of SDS and its progression to malignancy, which can be used to identify novel targets for AML/MDS therapy. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals New Bone Marrow Failure Genes: DNAJC21 and ERCC6L2

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-22-SCI-22
Author(s):  
Inderjeet Dokal
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Nuclear Export ◽  
Conflicts Of Interest ◽  
Excision Repair ◽  
Bone Marrow Failure ◽  
Retinal Dystrophy ◽  
Ribosomal Subunit ◽  
Genotoxic Stress ◽  
Biallelic Mutations

A significant number of cases with bone marrow failure present with one or more extra-hematopoietic abnormality. This suggests a constitutional or genetic basis, and yet many of them remain uncharacterized. Through exome sequencing, we have recently identified two sub groups of these cases, one defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21) and the other in ERCC6L2 (excision repair cross complementing 6 like-2). Patients with DNAJC21 mutations are characterized by global bone marrow failure in early childhood. They can also have a variable number of extra-hematopoietic abnormalities such as short stature and retinal dystrophy. The encoded protein associates with ribosomal RNA (rRNA) and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid patient cells exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced levels of rRNA. Characterisation of mutations has revealed impairment in interactions with cofactors (PA2G4, HSPA8 and ZNF622) involved in 60S maturation. DNAJC21 deficiency results in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles and increased cell death. Collectively these findings demonstrate that biallelic mutations in DNAJC21 cause disease due to defects in early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit. Patients harbouring biallelic ERCC6L 2 mutations are characterized by bone marrow failure (in childhood or early adulthood) and one or more extra-hematopoietic abnormality such as microcephaly. Knockdown of ERCC6L2 in human cells significantly reduces their viability upon exposure to the DNA damaging agent irofulven but not etoposide and camptothecin suggesting a role in nucleotide excision repair. ERCC6L2 knockdown cells and patient cells harbouring biallelic ERCC6L2 mutations also display H2AX phosphorylation that significantly increases upon genotoxic stress, suggesting an early DNA damage response. ERCC6L2 is seen to translocate to mitochondria as well as the nucleus in response to DNA damage and its knockdown induces intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger, N-acetyl-cysteine, attenuates the irofulven-induced cytotoxicity in ERCC6L2 knockdown cells and abolishes its traffic to mitochondria and nucleus in response to this DNA damaging agent. Collectively, these observations suggest that ERCC6L2has a pivotal rolein DNA repair and mitochondrial function. In conclusion, ERCC6L2 and DNAJC21 have an important role in maintaining genomic stability and ribosome biogenesis, respectively. They bring into focus new biological connections/pathways whose constitutional disruption is associated with defective hematopoiesis since patients harbouring germline biallelic mutations in these genes uniformly have bone marrow failure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Stepwise maturation of the peptidyl transferase region of human mitoribosomes

2021 ◽  
Author(s):  
Tea Lenarcic ◽  
Mateusz Jaskolowski ◽  
Marc Leibundgut ◽  
Alain Scaiola ◽  
Tanja Schoenhut ◽  
...  
Keyword(s):  
Quality Control ◽  
16S Rrna ◽  
Active Site ◽  
Critical Role ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Ribosome Assembly ◽  
Peptidyl Transferase ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Ribosome

Mitochondrial ribosomes are specialized for the synthesis of membrane proteins responsible for oxidative phosphorylation. Mammalian mitoribosomes diverged considerably from the ancestral bacterial ribosomes and feature dramatically reduced ribosomal RNAs. Structural basis of the mammalian mitochondrial ribosome assembly is currently not understood. Here we present eight distinct assembly intermediates of the human large mitoribosomal subunit involving 7 assembly factors. We discover that NSUN4-MTERF4 dimer plays a critical role in the process by stabilizing the 16S rRNA in a conformation that exposes the functionally important regions of rRNA for modification by MRM2 methyltransferase and quality control interactions with a conserved mitochondrial GTPase MTG2 that contacts the sarcin ricin loop and the immature active site. The successive action of these factors leads to the formation of the peptidyl transferase active site of the mitoribosome and the folding of the surrounding rRNA regions responsible for interactions with tRNAs and the small ribosomal subunit.

scholarly journals A DEAD-box protein regulates ribosome assembly through control of ribosomal protein synthesis

2019 ◽  
Vol 47 (15) ◽  
pp. 8193-8206 ◽  
Author(s):  
Isabelle Iost ◽  
Chaitanya Jain
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Proteins ◽  
Ribosomal Subunit ◽  
Large Family ◽  
Ribosome Assembly ◽  
Protein Abundance ◽  
Ribosomal Assembly ◽  
Dead Box ◽  
Ribosomal Protein Synthesis ◽  
Intrinsic Transcription Termination

Abstract DEAD-box proteins (DBPs) comprise a large family of proteins that most commonly have been identified as regulators of ribosome assembly. The Escherichia coli DBP, SrmB, represents a model bacterial DBP whose absence impairs formation of the large ribosomal subunit (LSU). To define the basis for SrmB function, suppressors of the ribosomal defect of ΔsrmB strains were isolated. The major class of suppressors was found to map to the 5′ untranslated region (UTR) of the rplM-rpsI operon, which encodes the ribosomal proteins (r-proteins) L13 and S9. An analysis of protein abundance indicated that both r-proteins are under-produced in the ΔsrmB strain, but are increased in these suppressors, implicating r-protein underproduction as the molecular basis for the observed ribosomal defects. Reduced r-protein synthesis was determined to be caused by intrinsic transcription termination within the rplM 5′ UTR that is abrogated by SrmB. These results reveal a specific mechanism for DBP regulation of ribosomal assembly, indirectly mediated through its effects on r-protein expression.

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