Article thumbnail

Angelman Syndrome Protein UBE3A Interacts with Primary Microcephaly Protein ASPM, Localizes to Centrosomes and Regulates Chromosome Segregation

By Pooja Singhmar and Arun Kumar

Abstract

Many proteins associated with the phenotype microcephaly have been localized to the centrosome or linked to it functionally. All the seven autosomal recessive primary microcephaly (MCPH) proteins localize at the centrosome. Microcephalic osteodysplastic primordial dwarfism type II protein PCNT and Seckel syndrome (also characterized by severe microcephaly) protein ATR are also centrosomal proteins. All of the above findings show the importance of centrosomal proteins as the key players in neurogenesis and brain development. However, the exact mechanism as to how the loss-of-function of these proteins leads to microcephaly remains to be elucidated. To gain insight into the function of the most commonly mutated MCPH gene ASPM, we used the yeast two-hybrid technique to screen a human fetal brain cDNA library with an ASPM bait. The analysis identified Angelman syndrome gene product UBE3A as an ASPM interactor. Like ASPM, UBE3A also localizes to the centrosome. The identification of UBE3A as an ASPM interactor is not surprising as more than 80% of Angelman syndrome patients have microcephaly. However, unlike in MCPH, microcephaly is postnatal in Angelman syndrome patients. Our results show that UBE3A is a cell cycle regulated protein and its level peaks in mitosis. The shRNA knockdown of UBE3A in HEK293 cells led to many mitotic abnormalities including chromosome missegregation, abnormal cytokinesis and apoptosis. Thus our study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis for the first time. We suggest that a defective chromosome segregation mechanism is responsible for the development of microcephaly in Angelman syndrome

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3102111
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2005). A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size.
  2. (1995). A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase.
  3. (2003). Angelman syndrome: a review of the clinical and genetic aspects.
  4. (2007). ASPM and citron kinase colocalize to the midbody ring during cytokinesis.
  5. (2002). ASPM is a major determinant of cerebral cortical size.
  6. (2009). CDK5RAP2 is required for spindle checkpoint function.
  7. (2010). Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors.
  8. (2005). Centrosome control of the cell cycle.
  9. (2002). Citron-kinase, a protein essential to cytokinesis in neuronal progenitors, is deleted in the flathead mutant rat.
  10. (1997). De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.
  11. (2008). Differential regulation of centrosome integrity by DNA damage response proteins.
  12. (2006). Does aneuploidy cause cancer?
  13. (2008). From centriole biogenesis to cellular function: centrioles are essential for cell division at critical developmental stages.
  14. (2004). Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.
  15. (2007). HECT E3s and human disease.
  16. (2003). Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression.
  17. (2009). Identification of annexin A1 as a novel substrate for E6AP-mediated ubiquitylation.
  18. (1999). Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination.
  19. (2002). Identification of microcephalin, a protein implicated in determining the size of the human brain.
  20. (2006). Microcephalin encodes a centrosomal protein.
  21. (1998). Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.
  22. (1990). Mutations at the asp locus of Drosophila lead to multiple free centrosomes in syncytial embryos but restrict centrosome duplication in larval neuroblasts.
  23. (2010). Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4.
  24. (2009). Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly.
  25. (2008). Mutations in the pericentrin (PCNT) gene cause primordial dwarfism.
  26. (2010). Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture.
  27. (2007). Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly.
  28. (2009). NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Ga.
  29. (2006). Pa ¨a ¨bo S, Huttner WB
  30. (2003). Protein truncating mutations in ASPM cause variable reduction in brain size.
  31. (1998). Spindle self-organization and cytokinesis during male meiosis in asterless mutants of Drosophila melanogaster.
  32. (2005). The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein.
  33. (2009). The molecular landscape of ASPM mutations in primary microcephaly.
  34. (1999). The role of cell death in regulating the size and shape of the mammalian forebrain.
  35. (1998). The SIL gene is required for mouse embryonic axial development and left-right specification.
  36. (2007). The zebra fish cassiopeia mutant reveals that SIL is required for mitotic spindle organization.
  37. (2010). Tissuespecific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome.
  38. (1997). UBE3A/E6-AP mutations cause Angelman syndrome.
  39. (2007). Ubiquitin-dependent proteolysis of trihydrophobin 1 (TH1) by the human papilloma virus E6-associated protein (E6-AP).
  40. (2010). WDR62 is associated with the spindle pole and is mutated in human microcephaly.