eIF2γ Mutation that Disrupts eIF2 Complex Integrity Links Intellectual Disability to Impaired Translation Initiation

Borck, Guntram; Shin, Byung‐Sik; Stiller, Barbara; Mimouni-Bloch, Aviva; Thiele, Holger; Kim, Joo-Ran; Thakur, Meghna; Skinner, Cindy; Aschenbach, Lara; Smirin‐Yosef, Pola; Har‐Zahav, Adi; Nürnberg, Gudrun; Altmüller, Janine; Frommolt, Peter; Hofmann, Kay; Konen, Osnat; Nürnberg, Peter; Münnich, Arnold; Schwartz, Charles E.; Gothelf, Doron; Colleaux, Laurence; Dever, Thomas E.; Kubisch, Christian; Basel‐Vanagaite, Lina

doi:10.1016/j.molcel.2012.09.005

Cited by 73 publications

(117 citation statements)

References 24 publications

(30 reference statements)

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“…Some examples include pontocerebellar hypoplasias, Pol III-related leukodystrophies, X-linked intellectual disability, and leukoencephalopathy with vanishing white matter (Bugiani et al 2010;Namavar et al 2011;Borck et al 2012;Daoud et al 2013). Complete inactivation of processes such as translation initiation or tRNA transcription is not compatible with life, suggesting that most disease-causing mutations are hypomorphs.…”

Section: Discussionmentioning

confidence: 99%

BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

et al. 2015

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RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.

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Section: Discussionmentioning

confidence: 99%

BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

et al. 2015

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“…4A). eIF2 and its control by phosphorylation and guanine nucleotide exchange are critical to various cellular processes and dysfunction of eIF2 is the cause of human diseases (42,43). Cdc123-mediated biogenesis of eIF2 might provide additional opportunities for regulation.…”

Section: Discussionmentioning

confidence: 99%

Translation Initiation Requires Cell Division Cycle 123 (Cdc123) to Facilitate Biogenesis of the Eukaryotic Initiation Factor 2 (eIF2)

Perzlmaier

Richter

Seufert

2013

Journal of Biological Chemistry

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Background:The eukaryotic translation initiation factor 2 (eIF2) is a heterotrimeric G-protein.Results: Cdc123, a conserved cell proliferation protein, binds the unassembled eIF2␥ subunit to promote eIF2 complex formation. Conclusion: Cdc123 is a specific eIF2 assembly factor indispensable for the onset of protein synthesis. Significance: This study describes a novel step in the eukaryotic translation initiation pathway.

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“…The N-terminal a-helix, which is unstructured in the free form of aIF2b, binds to the backside of the aIF2g GTP-binding (G) domain in the aIF2 complex (Sokabe et al 2006;Yatime et al 2007). Point mutations in this helix of yeast eIF2b, as well as in the docking site on yeast eIF2g, disrupt eIF2 complex formation and confer Gcd 2 and Sui 2 phenotypes (Hashimoto et al 2002;Borck et al 2012). In the archaeal aIF2 complex, the C-terminal zinc-binding domain of aIF2b packs against the central a-b domain (Sokabe et al 2006;Yatime et al 2007).…”

Section: Ternary Complex Formationmentioning

confidence: 99%

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

2016

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In this review, we provide an overview of protein synthesis in the yeast Saccharomyces cerevisiae. The mechanism of protein synthesis is well conserved between yeast and other eukaryotes, and molecular genetic studies in budding yeast have provided critical insights into the fundamental process of translation as well as its regulation. The review focuses on the initiation and elongation phases of protein synthesis with descriptions of the roles of translation initiation and elongation factors that assist the ribosome in binding the messenger RNA (mRNA), selecting the start codon, and synthesizing the polypeptide. We also examine mechanisms of translational control highlighting the mRNA cap-binding proteins and the regulation of GCN4 and CPA1 mRNAs.

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eIF2γ Mutation that Disrupts eIF2 Complex Integrity Links Intellectual Disability to Impaired Translation Initiation

Cited by 73 publications

References 24 publications

BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

Translation Initiation Requires Cell Division Cycle 123 (Cdc123) to Facilitate Biogenesis of the Eukaryotic Initiation Factor 2 (eIF2)

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

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