We recently described a signal transduction pathway that contributes to androgen receptor (AR) regulation based on site-specific ADP-ribosylation by PARP7, a mono-ADP-ribosyltransferase implicated in several human cancers. ADP-ribosylated AR is recognized by PARP9/DTX3L, a heterodimeric complex that contains an ADP-ribose reader (PARP9) and a ubiquitin E3 ligase (DTX3L). Here, we have characterized the cellular and biochemical requirements for AR ADP-ribosylation by PARP7. We found that the reaction requires nuclear localization of PARP7 and an agonist-induced conformation of AR. PARP7 contains a Cys3His1-type zinc finger (ZF), which also is critical for AR ADP-ribosylation. The Parp7 ZF is required for efficient nuclear import by a nuclear localization signal encoded in PARP7, but rescue experiments indicate the ZF makes a contribution to AR ADP-ribosylation that is separable from the effect on nuclear transport. ZF mutations do not detectably reduce PARP7 catalytic activity and binding to AR, but they do result in the loss of PARP7 enhancement of AR-dependent transcription of the MYBPC1 gene. Our data reveals critical roles for AR conformation and the PARP7 ZF in AR ADP-ribosylation and AR-dependent transcription.

中文翻译：

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PARP7单ADP-核糖基化细胞核中雄激素受体的激动剂构象

我们最近描述了一种信号转导途径，该途径有助于基于 PARP7 的位点特异性 ADP-核糖基化调节雄激素受体 (AR)，PARP7 是一种与几种人类癌症有关的单 ADP-核糖基转移酶。ADP 核糖基化 AR 被 PARP9/DTX3L 识别，这是一种异二聚体复合物，包含一个 ADP 核糖阅读器 (PARP9) 和一个泛素 E3 连接酶 (DTX3L)。在这里，我们已经描述了 PARP7 对 AR ADP 核糖基化的细胞和生化要求。我们发现该反应需要 PARP7 的核定位和激动剂诱导的 AR 构象。PARP7 包含一个 Cys3His1 型锌指 (ZF)，这对 AR ADP 核糖基化也很重要。Parp7 ZF 是通过 PARP7 编码的核定位信号进行有效核输入所必需的，但救援实验表明 ZF 对 AR ADP 核糖基化的贡献与对核运输的影响是分开的。ZF 突变不会显着降低 PARP7 催化活性和与 AR 的结合，但它们确实会导致 MYBPC1 基因的 AR 依赖性转录的 PARP7 增强丧失。我们的数据揭示了 AR 构象和 PARP7 ZF 在 AR ADP 核糖基化和 AR 依赖性转录中的关键作用。