EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Tan, Sophie; Kermasson, Laëtitia; Hoslin, Angela; Jaako, Pekka; Faille, Alexandre; Acevedo-Arozena, Abraham; Lengliné, Étienne; Ranta, Dana; Poirée, Maryline; Fenneteau, Odile; Pointe, Hubert Ducou Le; Fumagalli, Stefano; Beaupain, Blandine; Nitschké, Patrick; Bôle‐Feysot, Christine; Villartay, Jean‐Pierre de; Bellanné‐Chantelot, Christine; Donadieu, Jean; Kannengiesser, Caroline; Warren, Alan J.; Revy, Patrick

doi:10.1182/blood.2018893404

Cited by 55 publications

(79 citation statements)

References 52 publications

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“…EFL1 encodes a cytoplasmic GTPase that acts in concert with Sdo1, the yeast homolog of the Shwachman–Diamond syndrome protein, to promote release of Tif6 from 60S ribosomal subunits during their final maturation (Menne et al , ). Loss of one copy of the human EIF6 gene is a recurrent finding in bone marrow cells of Shwachman–Diamond syndrome patients and is associated with a relatively benign clinical course (Pressato et al , ; Valli et al , ), suggesting that this bypass suppressor mechanism is conserved from yeast to humans (Weis et al , ; Tan et al , ), and supporting a rationale for the development of small‐molecule eIF6 suppressor mimics for the treatment of Shwachman–Diamond syndrome.…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of bypass suppression of essential genes

Leeuwen

Pons

Tan

et al. 2020

Molecular Systems Biology

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Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole‐genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations underlying bypass suppression. Dispensable essential genes often had paralogs, were enriched for genes encoding membrane‐associated proteins, and were depleted for members of protein complexes. Functionally related genes frequently drove the bypass suppression interactions. These gene properties were predictive of essential gene dispensability and of specific suppressors among hundreds of genes on aneuploid chromosomes. Our findings identify yeast's core essential gene set and reveal that the properties of dispensable essential genes are conserved from yeast to human cells, correlating with human genes that display cell line‐specific essentiality in the Cancer Dependency Map (DepMap) project.

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Section: Discussionmentioning

confidence: 99%

Systematic analysis of bypass suppression of essential genes

Leeuwen

Pons

Tan

et al. 2020

Molecular Systems Biology

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“…This would suggest that, if the HR defect associated with SBDS mutation contributes to malignant progression, then those with SDS due to EFL1 mutations would not have an increased risk of MDS/AML. None of the 10 patients with biallelic EFL1 variants and SDS have been reported to have MDS or AML (7)(8)(9). Nevertheless, the numbers of patients are too small to draw conclusions at this time.…”

Section: Discussionmentioning

confidence: 89%

“…SBDS activates EFL1 to mediate the eviction of eIF6 from the 60S subunit. Therefore, as an alternative approach to address the importance of ribosome joining, we examined the impact of EFL1 depletion on HR (8). Similar to eIF6 depletion and in contrast to SBDS depletion, EFL1 depletion did not reduce HR efficiency ( Figure, 3C and D).…”

Section: Burwick Et Al Demonstrated That Knockdown Of Eif6 Improved mentioning

confidence: 99%

“…One of these is Shwachman-Diamond syndrome (SDS), an autosomal recessive multisystem disorder with major clinical features of neutropenia, exocrine pancreatic dysfunction, metaphyseal dysplasia, and short stature (5). Approximately 90% of patients with SDS have pathogenic variants in SBDS (6), and, recently, some patients have been found to harbor pathogenic variants in EFL1 (7)(8)(9). Consistent with the roles of SBDS and EFL1 in the eviction of eIF6 from the surface of the 60S ribosomal subunit, cells from patients bearing SBDS or EFL1 mutations have defects in ribosomal subunit joining (8,10,11), and cells with deficient or mutant SBDS protein have a global reduction of protein synthesis (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Asik¹,

Chatterjee²,

Bertuch³

2020

Preprint

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Shwachman-Diamond syndrome (SDS) and Diamond-Blackfan anemia (DBA) are ribosomopathies characterized by impaired hematopoiesis and cancer predisposition. The mechanisms underlying cancer predisposition in these disorders are not well understood. We found that LCLs derived from patients with SDS or DBA had a prolonged DNA damage response and hypersensitivity to ionizing radiation, suggesting impaired DNA double strand break (DSB) repair. Consistent with this, depletion of SBDS and RPS19, the most common etiologic factors in SDS and DBA, respectively, resulted in reduced homologous recombination (HR) in HCT116 and U2OS cells. Surprisingly, depletion of EFL1, which functions with SBDS in ribosome biogenesis, did not impair HR and depletion of eIF6, which restores ribosome joining in SBDS-depleted cells, did not rescue the HR defect associated with SBDS depletion. Instead, we found SBDS and RPS19 recruitment to sites of DSBs suggesting that SBDS and RPS19 have more proximate roles in regulating HR, independent of their ribosomal functions. We propose that reduced HR shifts DSB repair toward error-prone NHEJ and this may contribute to oncogenesis in SDS and DBA. Additionally, we found SBDS and RPS19 depleted cells were hypersensitive to PARP inhibition, potentially uncovering a therapeutic target for SDS- and DBA-associated malignancies.

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“…The majority of SDS patients have loss of function mutations in SBDS (SDS1, OMIM #260400) [16]. The best characterized function of SBDS is its role in the release and recycling of eIF6 from pre-60S ribosomes, a process that also involves the GTPase activity of Elongation Factor-Like 1 (EFL1) (SDS2, OMIM # 617941) [17][18][19][20]. The release of eIF6 is a required step in the maturation of the 60S ribosomal subunit [1,3,21,22].…”

Section: Introductionmentioning

confidence: 99%

Disruption in iron homeostasis and impaired activity of iron-sulfur cluster containing proteins in the yeast model of Shwachman-Diamond syndrome

et al. 2020

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Background Shwachman-Diamond syndrome (SDS) is a congenital disease that affects the bone marrow, skeletal system, and pancreas. The majority of patients with SDS have mutations in the SBDS gene, involved in ribosome biogenesis as well as other processes. A Saccharomyces cerevisiae model of SDS, lacking Sdo1p the yeast orthologue of SBDS, was utilized to better understand the molecular pathogenesis in the development of this disease. Results Deletion of SDO1 resulted in a three-fold over-accumulation of intracellular iron. Phenotypes associated with impaired iron-sulfur (ISC) assembly, up-regulation of the high affinity iron uptake pathway, and reduced activities of ISC containing enzymes aconitase and succinate dehydrogenase, were observed in sdo1∆ yeast. In cells lacking Sdo1p, elevated levels of reactive oxygen species (ROS) and protein oxidation were reduced with iron chelation, using a cell impermeable iron chelator. In addition, the low activity of manganese superoxide dismutase (Sod2p) seen in sdo1∆ cells was improved with iron chelation, consistent with the presence of reactive iron from the ISC assembly pathway. In yeast lacking Sdo1p, the mitochondrial voltage-dependent anion channel (VDAC) Por1p is over-expressed and its deletion limits iron accumulation and increases activity of aconitase and succinate dehydrogenase. Conclusions We propose that oxidative stress from POR1 over-expression, resulting in impaired activity of ISC containing proteins and disruptions in iron homeostasis, may play a role in disease pathogenesis in SDS patients.

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EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Cited by 55 publications

References 52 publications

Systematic analysis of bypass suppression of essential genes

Systematic analysis of bypass suppression of essential genes

Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Disruption in iron homeostasis and impaired activity of iron-sulfur cluster containing proteins in the yeast model of Shwachman-Diamond syndrome

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