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鉴定 PARP-7 的底物表明 MARylation 在卵巢癌细胞微管调控中的作用。

Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells.

机构信息

Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, United States.

Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, United States.

出版信息

Elife. 2021 Jan 21;10:e60481. doi: 10.7554/eLife.60481.

DOI:10.7554/eLife.60481
PMID:33475085
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7884071/
Abstract

PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose protein substrates and biological activities are poorly understood. We observed that mRNA levels are lower in ovarian cancer patient samples compared to non-cancerous tissue, but PARP-7 protein nonetheless contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g. growth, migration). Global gene expression analyses in ovarian cancer cells subjected to PARP-7 depletion indicate biological roles for PARP-7 in cell-cell adhesion and gene regulation. To identify the MARylated substrates of PARP-7 in ovarian cancer cells, we developed an NAD analog-sensitive approach, which we coupled with mass spectrometry to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including cell-cell adhesion and cytoskeletal proteins. Specifically, we found that PARP-7 MARylates α-tubulin to promote microtubule instability, which may regulate ovarian cancer cell growth and motility. In sum, we identified an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes.

摘要

PARP-7（TiPARP）是一种单（ADP-核糖基）转移酶，其蛋白质底物和生物学活性知之甚少。我们观察到，与非癌组织相比，卵巢癌患者样本中的 mRNA 水平较低，但 PARP-7 蛋白仍有助于卵巢癌细胞中的几种与癌症相关的生物学终点（例如生长、迁移）。卵巢癌细胞中 PARP-7 耗竭的全基因表达分析表明 PARP-7 在细胞-细胞黏附和基因调控中具有生物学作用。为了鉴定卵巢癌细胞中 PARP-7 的 MARylated 底物，我们开发了一种 NAD 类似物敏感的方法，我们将其与质谱法结合，以鉴定卵巢癌细胞中的 PARP-7 ADP-核糖基化蛋白质组，包括细胞-细胞黏附和细胞骨架蛋白。具体来说，我们发现 PARP-7 MARylates α-微管蛋白以促进微管不稳定，这可能调节卵巢癌细胞的生长和运动。总之，我们鉴定了一个广泛的 PARP-7 ADP-核糖基化蛋白质组，在与癌症相关的细胞表型中具有重要作用。

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