Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Cell Death Dis. 2020 Nov 3;11(11):946. doi: 10.1038/s41419-020-03068-7.
MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.
MCL1 是一种抗凋亡蛋白，通过调节内在凋亡来控制化学敏感性和细胞命运，已被确定为抗癌治疗开发中的高影响靶点。随着 MCL1 特异性抑制剂目前正在临床试验中，我们必须了解 MCL1 在细胞中的作用，特别是在靶向 Bcl-2 同源结构域 3（BH3）口袋时，MCL1 的中央区域介导凋亡调节。在这里，我们确定 MCL1 在外显子转录活性的控制中具有直接作用，该作用调节与 DNA 损伤反应、细胞凋亡和细胞周期进展相关的靶基因。这种相互作用是通过 p73 四聚化结构域中的反向 BH3（rBH3）基序介导的，该基序限制了 p73 在 DNA 上的组装。在这里，我们提供了一种 MCL1 对 p73 转录活性的蛋白质水平调节的新机制，同时也为研究 MCL1 抑制剂与铂类化疗药物联合应用奠定了基础。更广泛地说，这项工作扩展了 Bcl-2 家族信号在细胞命运调节之外的作用。
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