Department of Bioscience and Biotechnology, Sejong University, 98 Gunja-dong, Gwangjin-Gu, Seoul 143-747, Korea.
Mol Cell. 2013 Jul 25;51(2):200-10. doi: 10.1016/j.molcel.2013.06.005. Epub 2013 Jul 11.
Despite the importance of retinoic acid (RA) signaling and histone monoubiquitination in determining cell fate, the underlying mechanism linking the two processes is poorly explored. We describe that additional sex comb-like 1 (ASXL1) represses RA receptor activity by cooperating with BRCA1-associated protein 1 (BAP1), which contains the ubiquitin C-terminal hydrolase (UCH) domain. Both the UCH- and ASXL1-binding domains of BAP1 were required for cooperation. In contrast to Drosophila BAP1, mammalian BAP1 cleaved ubiquitin from histone H2B. As supported by BAP1 mutants, ASXL1 was critical for BAP1 recruitment to chromatin and its activation therein. ASXL1 requirement was supported using Asxl1 null mice embryonic fibroblasts. Both ASXL1 and BAP1 were downregulated during RA-induced P19 cell differentiation with concomitant increase of ubiquitinated H2B, leading to activation of Hox genes. Our data demonstrate the critical role of ASXL1 cooperation with BAP1 in cell differentiation through the regulation of RA signaling associated with H2B ubiquitination.
尽管视黄酸 (RA) 信号和组蛋白单泛素化在决定细胞命运方面非常重要，但将这两个过程联系起来的潜在机制还没有得到很好的探索。我们描述了额外的性梳样蛋白 1 (ASXL1) 通过与含有泛素 C 末端水解酶 (UCH) 结构域的 BRCA1 相关蛋白 1 (BAP1) 合作来抑制 RA 受体活性。BAP1 的 UCH 和 ASXL1 结合域都需要合作。与果蝇 BAP1 不同，哺乳动物 BAP1 从组蛋白 H2B 上切割泛素。BAP1 突变体的支持表明，ASXL1 对于 BAP1 招募到染色质及其在其中的激活至关重要。使用 Asxl1 缺失的小鼠胚胎成纤维细胞支持 Asxl1 的需求。在 RA 诱导的 P19 细胞分化过程中，ASXL1 和 BAP1 均下调，同时伴随着 H2B 的泛素化增加，导致 Hox 基因的激活。我们的数据表明，ASXL1 与 BAP1 合作通过调节与 H2B 泛素化相关的 RA 信号在细胞分化中发挥关键作用。
