Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability

Killian, Audrey; Meur, Nathalie Le; Sesboüé, Richard; Bourguignon, Jeannette; Bougeard, Gaëlle; Gautherot, Julien; Bastard, Christian; Frébourg, Thierry; Flaman, Jean–Michel

doi:10.1038/sj.onc.1207845

Cited by 64 publications

(72 citation statements)

References 35 publications

(38 reference statements)

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“…We have observed similar staining patterns for other Drosophila ORC subunits, including Orc1 and Orc2. Moreover, ORC was found in the nucleolus in human cells (31,32). These findings may indicate a potential interaction of ORC with components of the ribosome biogenesis pathway (31,33).…”

Section: Orc6 Mutant Is Defective In Dna Replication and Arrests In Bmentioning

confidence: 91%

Functional analysis of an Orc6 mutant in Drosophila

Balasov

Huijbregts

Chesnokov

2009

Proc. Natl. Acad. Sci. U.S.A.

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The origin recognition complex (ORC) is a 6-subunit complex required for the initiation of DNA replication in eukaryotic organisms. ORC is also involved in other cell functions. The smallest Drosophila ORC subunit, Orc6, is important for both DNA replication and cytokinesis. To study the role of Orc6 in vivo, the orc6 gene was deleted by imprecise excision of P element. Lethal alleles of orc6 are defective in DNA replication and also show abnormal chromosome condensation and segregation. The analysis of cells containing the orc6 deletion revealed that they arrest in both the G 1 and mitotic stages of the cell cycle. Orc6 deletion can be rescued to viability by a full-length Orc6 transgene. The expression of mutant transgenes of Orc6 with deleted or mutated C-terminal domain results in a release of mutant cells from G 1 arrest and restoration of DNA replication, indicating that the DNA replication function of Orc6 is associated with its N-terminal domain. However, these mutant cells accumulate at mitosis, suggesting that the C-terminal domain of Orc6 is important for the passage through the M phase. In a cross-species complementation experiment, the expression of human Orc6 in Drosophila Orc6 mutant cells rescued DNA replication, suggesting that this function of the protein is conserved among metazoans.DNA replication ͉ ORC ͉ Chromatin T he hexameric origin recognition complex (ORC) is an essential component for eukaryotic DNA replication. It was originally discovered in Saccharomyces cerevisiae, and subsequent studies both in yeast and in higher eukaryotes laid the foundation for understanding the functions of this important key initiation factor. ORC binds to origin sites in an ATP-dependent manner and directs the assembly of the prereplicative complex (pre-RC) at the origins (1, 2). ORC subunits and/or complete ORC complexes have also been identified in many metazoan species (1, 3), suggesting the existence of common mechanisms for the initiation of DNA replication in all eukaryotes. ORC genes are essential for cell survival. Mutational analysis of ORC-related genes in yeast and in higher eukaryotes reveals defects in DNA replication (reviewed in refs.

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Section: Orc6 Mutant Is Defective In Dna Replication and Arrests In Bmentioning

confidence: 91%

Functional analysis of an Orc6 mutant in Drosophila

Balasov

Huijbregts

Chesnokov

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…1C). ORC6L is a protein involved in the DNA replication complex and acts as an essential gene that coordinates chromosome replication and segregation with cytokinesis (23,24). The overexpression of ORC6L in colorectal tumors may indicate a strong association with the disease development.…”

Section: Discussionmentioning

confidence: 99%

Validation of biomarkers associated with 5-fluorouracil and thymidylate synthase in colorectal cancer

Formentini²,

Nakajima³

et al. 2008

Oncol Rep

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Abstract. Previous studies from our laboratory have identified a number of genes associated with chemosensitivity to 5-fluorouracil (5-FU) using an in vitro colon cancer cell line model. In this study, the in vivo significance of several marker genes in terms of prognostic potential was evaluated using colorectal cancer patient samples. Eight marker genes were selected based on their functional roles and significant fold changes in expression. They are SERTA domain containing 1 (SEI1), ribonucleotide reductase M2 polypeptide (RRM2), origin recognition complex, subunit 6 homolog-like (ORC6L), eukaryotic translation initiation factor 4E (EIF4E), thymidylate synthase (TS), SET and MYND domain containing 3 (SMYD3), Dickkopf homolog 4, and methyl-CpG binding domain protein 4 (MBD4). Forty-eight snap frozen clinical colorectal samples (24 normal and 24 paired colorectal cancer patient samples) were selected with detailed clinical followup information. cDNAs were synthesized and the expression levels of marker genes were quantified via qRT-PCR analysis. The statistical significance of these markers for disease prognosis was evaluated using the two-tailed paired Wilcoxon test. Survival curves were plotted according to the method of Kaplan-Meier and compared using the log-rank test. Based on the quantitative expression analysis, RRM2 (p=0.0001; 95% CI, 2.0-4.5), ORC6L (p=0.0001; 95% CI, 1.8-4.6), EIF4E (p=0.0002; 95% CI, 0.3-0.9), TS (p=0.0005; 95% CI, 0.7-2.2) and SMYD3 (p=0.0001; 95% CI, 0.8-1.5) were overexpressed in tumor tissues. However, the expression of SEI1 was decreased in tumors (p=0.02; 95% CI, 0.1-1.3), consistent with the function of SEI1 as a potential tumor suppressor. KaplanMeier survival analysis indicated that MBD4 is a significant prognostic factor for patient survival (p=0.03). MBD4 was a key protein involved in DNA methylation. The expression of TS was associated with tumor stage as it had a significantly higher expression level in UICC stage I and II compared to stage IV patients (p=0.03). MBD4 may be a potential novel prognostic marker for predicting patient survival for colorectal cancer.

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“…both ribosome biogenesis and cell cycle control (Iouk et al, 2001;Schaper et al, 2001;Du and Stillman, 2002;Killian et al, 2004). A gene encoding another member of this complex, pescadillo (pes), was among those displaying altered expression in sbds morphants.…”

Section: Loss Of Sbds Is Associated With a Broad Change In Ribosome-rmentioning

confidence: 99%

“…However, this view of RP transcription is likely to be an oversimplification, and evidence exists for uncoupling of individual RPs from otherwise coordinated expression. For example, both Rpl3 and Pes interact with another member of the yeast Pescadillo complex, Rrb1p (GRWD1 in human) (Iouk et al, 2001;Killian et al, 2004). The function of Rrb1p in ribosome biogenesis is linked to its physical interaction with Rpl3.…”

Section: Research Article Ribosome Biogenesis Genes In Pancreas Develmentioning

confidence: 99%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability

Cited by 64 publications

References 35 publications

Functional analysis of an Orc6 mutant in Drosophila

Functional analysis of an Orc6 mutant in Drosophila

Validation of biomarkers associated with 5-fluorouracil and thymidylate synthase in colorectal cancer

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

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