From the Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903.
the DNA Damage Response Laboratory, London Research Institute, Clare Hall, South Mimms, EN6 3LD Herts, United Kingdom.
J Biol Chem. 2013 Nov 8;288(45):32357-32369. doi: 10.1074/jbc.M113.459164. Epub 2013 Aug 6.
Activation of poly(ADP-ribose) polymerase (PARP) near sites of DNA breaks facilitates recruitment of DNA repair proteins and promotes chromatin relaxation in part through the action of chromatin-remodeling enzyme Amplified in Liver Cancer 1 (ALC1). Through proteomic analysis we find that ALC1 interacts after DNA damage with Tripartite Motif-containing 33 (TRIM33), a multifunctional protein implicated in transcriptional regulation, TGF-β signaling, and tumorigenesis. We demonstrate that TRIM33 is dynamically recruited to DNA damage sites in a PARP1- and ALC1-dependent manner. TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged retention of ALC1 at sites of DNA breaks. Conversely, overexpression of TRIM33 alleviates the DNA repair defects conferred by ALC1 overexpression. Thus, TRIM33 plays a role in PARP-dependent DNA damage response and regulates ALC1 activity by promoting its timely removal from sites of DNA damage.
聚（ADP-核糖）聚合酶（PARP）在 DNA 断裂部位的激活有助于招募 DNA 修复蛋白，并通过肝癌扩增因子 1（ALC1）等染色质重塑酶的作用促进染色质松弛。通过蛋白质组学分析，我们发现 ALC1 在 DNA 损伤后与包含三部分基序的 33 号蛋白（TRIM33）相互作用，TRIM33 是一种多功能蛋白，参与转录调控、TGF-β 信号转导和肿瘤发生。我们证明，TRIM33 以依赖 PARP1 和 ALC1 的方式动态募集到 DNA 损伤部位。缺乏 TRIM33 的细胞对 DNA 损伤的敏感性增强，并且 ALC1 在 DNA 断裂部位的保留时间延长。相反，TRIM33 的过表达减轻了 ALC1 过表达赋予的 DNA 修复缺陷。因此，TRIM33 在依赖 PARP 的 DNA 损伤反应中发挥作用，并通过促进其从 DNA 损伤部位的及时去除来调节 ALC1 的活性。
