title: Scmh1 has E3 ubiquitin ligase activity for geminin and histone H2A and regulates geminin stability directly or indirectly via transcriptional repression of Hoxa9 and Hoxb4.
abstract: Polycomb-group (PcG) complex 1 acts as an E3 ubiquitin ligase both for histone H2A to silence transcription and for geminin to regulate its stability. Scmh1 is a substoichiometric component of PcG complex 1 that provides the complex with an interaction domain for geminin. Scmh1 is unstable and regulated through the ubiquitin-proteasome system, but its molecular roles are unknown, so we generated Scmh1-deficient mice to elucidate its function. Loss of Scmh1 caused derepression of Hoxb4 and Hoxa9, direct targets of PcG complex 1-mediated transcriptional silencing in hematopoietic cells. Double knockdown of Hoxb4 and Hoxa9 or transduction of a dominant-negative Hoxb4N→A mutant caused geminin accumulation. Age-related transcriptional downregulation of derepressed Hoxa9 also leads to geminin accumulation. Transduction of Scmh1 lacking a geminin-binding domain restored derepressed expression of Hoxb4 and Hoxa9 but did not downregulate geminin like full-length Scmh1. Each of Hoxb4 and Hoxa9 can form a complex with Roc1-Ddb1-Cul4a to act as an E3 ubiquitin ligase for geminin. We suggest that geminin dysregulation may be restored by derepressed Hoxb4 and Hoxa9 in Scmh1-deficient mice. These findings suggest that PcG and a subset of Hox genes compose a homeostatic regulatory system for determining expression level of geminin.
authors.affiliation: Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Shin'ichiro
authors.initials: S
authors.lastname: Yasunaga
authors.forename: Motoaki
authors.initials: M
authors.lastname: Ohtsubo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohno
authors.forename: Keita
authors.initials: K
authors.lastname: Saeki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kurogi
authors.forename: Miki
authors.initials: M
authors.lastname: Tanaka-Okamoto
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ishizaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Shirai
authors.forename: Keichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Hugh W
authors.initials: HW
authors.lastname: Brock
authors.forename: Jun
authors.initials: J
authors.lastname: Miyoshi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D064248:Geminin; D055786:Gene Knockout Techniques; D005801:Genes, Homeobox; D056426:Genetic Loci; D006410:Hematopoiesis; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D063146:Polycomb-Group Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D064248:Geminin; C577997:Gmnn protein, mouse; D006657:Histones; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; C570430:Scmh1 protein, mouse; D014157:Transcription Factors; D025801:Ubiquitin; C097899:homeobox protein HOXA9; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex