Translational mechanisms at work in the cohesinopathies

Chromosome cohesion, mediated by the cohesin complex, is essential for the process of chromosome segregation. Mutations in cohesin and its regulators are associated with a group of human diseases known as the cohesinopathies. These diseases are characterized by defects in head, face, limb, and heart development, mental retardation, and poor growth. The developmental features of the diseases are not well explained by defects in chromosome segregation, but instead are consistent with changes in gene expression during embryogenesis. Thus a central question to understanding the cohesinopathies is how mutations in cohesin lead to changes in gene expression. One of the prevailing models is that cohesin binding to promoters and enhancers directly regulates transcription. I propose that in addition cohesin may influence gene expression via translational mechanisms. If true, cohesinopathies may be related in etiology to another group of human diseases known as ribosomopathies, diseases caused by defects in ribosome biogenesis. By considering this possibility we can more fully evaluate causes and treatments for the cohesinopathies.

[1]  B. Paw,et al.  L-Leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway. , 2012, Blood.

[2]  S. Karlsson,et al.  Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia. , 2012, Blood.

[3]  Gabriele Gillessen-Kaesbach,et al.  HDAC8 mutations in Cornelia de Lange Syndrome affect the cohesin acetylation cycle , 2012, Nature.

[4]  I. Krantz,et al.  RAD21 mutations cause a human cohesinopathy. , 2012, American journal of human genetics.

[5]  Shifeng Xue,et al.  Specialized ribosomes: a new frontier in gene regulation and organismal biology , 2012, Nature Reviews Molecular Cell Biology.

[6]  Brian D. Slaughter,et al.  Cohesin Proteins Promote Ribosomal RNA Production and Protein Translation in Yeast and Human Cells , 2012, PLoS genetics.

[7]  K. Monahan,et al.  Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression , 2012, Proceedings of the National Academy of Sciences.

[8]  C. De Virgilio,et al.  Leucyl-tRNA synthetase controls TORC1 via the EGO complex. , 2012, Molecular cell.

[9]  Sunghoon Kim,et al.  Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway , 2012, Cell.

[10]  Jean-Christophe Aude,et al.  Genomic binding of Pol III transcription machinery and relationship with TFIIS transcription factor distribution in mouse embryonic stem cells , 2011, Nucleic acids research.

[11]  Davide Ruggero,et al.  rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells. , 2011, Molecular cell.

[12]  A. Lander,et al.  Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome , 2011, PLoS biology.

[13]  C. Stumpf,et al.  The cancerous translation apparatus. , 2011, Current opinion in genetics & development.

[14]  C. Print,et al.  A Zebrafish Model of Roberts Syndrome Reveals That Esco2 Depletion Interferes with Development by Disrupting the Cell Cycle , 2011, PloS one.

[15]  Shifeng Xue,et al.  Ribosome-Mediated Specificity in Hox mRNA Translation and Vertebrate Tissue Patterning , 2011, Cell.

[16]  L. Hoefsloot,et al.  Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome , 2011, Nature Genetics.

[17]  F. Boisvert,et al.  The Nucleolus under Stress , 2010, Molecular Cell.

[18]  Kathryn E. Crosier,et al.  Positive regulation of c-Myc by cohesin is direct, and evolutionarily conserved. , 2010, Developmental biology.

[19]  J. Gerton,et al.  Regulators of the cohesin network. , 2010, Annual review of biochemistry.

[20]  B. Ebert,et al.  Ribosomopathies: human disorders of ribosome dysfunction. , 2010, Blood.

[21]  Martin Mokrejs,et al.  IRESite—a tool for the examination of viral and cellular internal ribosome entry sites , 2009, Nucleic Acids Res..

[22]  S. Thompson,et al.  RPS25 is essential for translation initiation by the Dicistroviridae and hepatitis C viral IRESs. , 2009, Genes & development.

[23]  J. Gerton,et al.  Cohesinopathy mutations disrupt the subnuclear organization of chromatin , 2009, The Journal of cell biology.

[24]  R. Wolthuis,et al.  The Cellular Phenotype of Roberts Syndrome Fibroblasts as Revealed by Ectopic Expression of ESCO2 , 2009, PloS one.

[25]  B. Hallgrímsson,et al.  Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl +/− Mouse, a Model of Cornelia de Lange Syndrome , 2009, PLoS genetics.

[26]  V. Mootha,et al.  Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans , 2009, Proceedings of the National Academy of Sciences.

[27]  Zhe Zhang,et al.  Transcriptional Dysregulation in NIPBL and Cohesin Mutant Human Cells , 2009, PLoS biology.

[28]  I. Krantz,et al.  Cohesin and human disease. , 2008, Annual review of genomics and human genetics.

[29]  T. Itoh,et al.  Identification of cis-acting sites for condensin loading onto budding yeast chromosomes. , 2008, Genes & development.

[30]  Francesca Forzano,et al.  The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. , 2008, Human molecular genetics.

[31]  Michael Ashburner,et al.  The ribosomal protein genes and Minute loci of Drosophila melanogaster , 2007, Genome Biology.

[32]  Wei Xu,et al.  Impaired Control of IRES-Mediated Translation in X-Linked Dyskeratosis Congenita , 2006, Science.

[33]  E. Jabs,et al.  Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion , 2005, Nature Genetics.

[34]  I. Krantz,et al.  NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. , 2004, American journal of human genetics.

[35]  I. Krantz,et al.  Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B , 2004, Nature Genetics.

[36]  Tom Strachan,et al.  NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome , 2004, Nature Genetics.

[37]  Nancy Hopkins,et al.  Many Ribosomal Protein Genes Are Cancer Genes in Zebrafish , 2004, PLoS biology.

[38]  L. Siracusa,et al.  The Cohesin SMC3 Is a Target the for β-Catenin/TCF4 Transactivation Pathway* , 2003, Journal of Biological Chemistry.

[39]  L. Siracusa,et al.  The cohesin SMC3 is a target the for beta-catenin/TCF4 transactivation pathway. , 2003, The Journal of biological chemistry.

[40]  K. Nasmyth,et al.  Cohesins: Chromosomal Proteins that Prevent Premature Separation of Sister Chromatids , 1997, Cell.