Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
Leiden University Medical Center, Department of Human Genetics, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
Mol Cell. 2019 Aug 8;75(3):483-497.e9. doi: 10.1016/j.molcel.2019.06.002. Epub 2019 Jun 25.
In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.
在哺乳动物中，约有 100 种去泛素化酶作用于约 20000 个细胞内泛素化位点。去泛素化酶通常被认为是组成性激活的，具有有限的调节和靶向能力。BRCA1-A 和 BRISC 复合物参与 DNA 双链断裂修复和免疫信号转导，包含赖氨酸-63 连接特异性 BRCC36 亚基，该亚基分别由支架亚基 ABRAXAS 和 ABRO1 功能化。BRCA1-A 和 BRISC 功能的分子基础目前尚不清楚。在这里，我们展示了在 BRCA1-A 复合物结构中，ABRAXAS 整合了 DNA 修复蛋白 RAP80，并提供了一个高亲和力的结合位点，将肿瘤抑制因子 BRCA1 与断裂位点隔离开来。在 BRISC 结构中，ABRO1 结合代谢酶 SHMT2α，这种酶能够使肿瘤在缺氧环境中生长，我们发现这阻止了 BRCC36 结合和切割泛素链。我们的工作解释了 BRCC36 DUB 家族的模块性，不同的接头亚基赋予了多样化的靶向和调节功能。
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