Wang Lei, Charroux Bernard, Kerridge Stephen, Tsai Chih-Cheng
Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA.
EMBO Rep. 2008 Jun;9(6):555-62. doi: 10.1038/embor.2008.67. Epub 2008 May 2.
Atrophin family proteins, including the vertebrate arginine-glutamic acid dipeptide repeats protein (RERE) and Drosophila Atrophin (Atro), constitute a new class of nuclear receptor corepressors. Both RERE and Atro share the ELM2 (EGL-27 and MTA1 homology 2) and SANT (SWI3/ADA2/N-CoR/TFIII-B) domains, which are also present in other important transcriptional cofactors. Here, we report that the SANT domain in RERE binds to the histone methyltransferase G9a, and that both the ELM2 and SANT domains orchestrate molecular events that lead to a stable methylation of histone H3-lysine 9. We establish the physiological relevance of these interactions among Atrophin, G9a, and histone deacetylases 1 and 2 in Drosophila by showing that these proteins localize to overlapping chromosomal loci, and act together to suppress wing vein and melanotic-mass formation. This study not only shows a new function of the SANT domain and establishes its connection with the ELM2 domain, but also implies that a similar strategy is used by other ELM2-SANT proteins to repress gene transcription and to exert biological effects.
萎缩蛋白家族蛋白，包括脊椎动物的精氨酸 - 谷氨酸二肽重复蛋白（RERE）和果蝇萎缩蛋白（Atro），构成了一类新的核受体共抑制因子。RERE和Atro都具有ELM2（EGL - 27和MTA1同源结构域2）和SANT（SWI3/ADA2/N - CoR/TFIII - B）结构域，这些结构域也存在于其他重要的转录辅因子中。在此，我们报告RERE中的SANT结构域与组蛋白甲基转移酶G9a结合，并且ELM2和SANT结构域共同协调导致组蛋白H3赖氨酸9稳定甲基化的分子事件。我们通过证明这些蛋白定位于重叠的染色体位点，并共同作用抑制翅脉和黑色素瘤块的形成，确定了果蝇中萎缩蛋白、G9a以及组蛋白去乙酰化酶1和2之间这些相互作用的生理相关性。这项研究不仅揭示了SANT结构域的新功能并建立了其与ELM2结构域的联系，还暗示其他ELM2 - SANT蛋白采用类似策略来抑制基因转录并发挥生物学效应。
