Yasunaga S, Ohtsubo M, Ohno Y, Saeki K, Kurogi T, Tanaka-Okamoto M, Ishizaki H, Shirai M, Mihara K, Brock HW, Miyoshi J, Takihara Y
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 sub-stoichiometric 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 down-regulation 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 down-regulate 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.