Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, 755-8505, Japan.
Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.
Nat Commun. 2017 Nov 21;8(1):1638. doi: 10.1038/s41467-017-01807-7.
Poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA repair, chromatin structure, and transcription. However, the mechanisms that regulate PARP1 distribution on DNA are poorly understood. Here, we show that heat shock transcription factor 1 (HSF1) recruits PARP1 through the scaffold protein PARP13. In response to DNA damage, activated and auto-poly-ADP-ribosylated PARP1 dissociates from HSF1-PARP13, and redistributes to DNA lesions and DNA damage-inducible gene loci. Histone deacetylase 1 maintains PARP1 in the ternary complex by inactivating PARP1 through deacetylation. Blocking ternary complex formation impairs redistribution of PARP1 during DNA damage, which reduces gene expression and DNA repair. Furthermore, ternary complex formation and PARP1 redistribution protect cells from DNA damage by promoting DNA repair, and support growth of BRCA1-null mammary tumors, which are sensitive to PARP inhibitors. Our findings identify HSF1 as a regulator of genome integrity and define this function as a guarding mechanism for a specific type of mammary tumorigenesis.
聚（ADP-核糖）聚合酶 1（PARP1）参与 DNA 修复、染色质结构和转录。然而，调节 PARP1 在 DNA 上分布的机制还知之甚少。在这里，我们表明热休克转录因子 1（HSF1）通过支架蛋白 PARP13 招募 PARP1。在 DNA 损伤反应中，激活的和自身多聚 ADP-核糖基化的 PARP1 从 HSF1-PARP13 上解离，并重新分布到 DNA 损伤部位和 DNA 损伤诱导基因座。组蛋白去乙酰化酶 1 通过去乙酰化使 PARP1 失活，从而将 PARP1 维持在三元复合物中。阻断三元复合物的形成会损害 DNA 损伤过程中 PARP1 的重新分布，从而降低基因表达和 DNA 修复。此外，三元复合物的形成和 PARP1 的重新分布通过促进 DNA 修复来保护细胞免受 DNA 损伤，并支持对 PARP 抑制剂敏感的 BRCA1 缺失型乳腺肿瘤的生长。我们的发现确定了 HSF1 作为基因组完整性的调节剂，并将这一功能定义为特定类型的乳腺肿瘤发生的保护机制。
