PARP1调控干细胞和癌细胞中KLF4介导的端粒酶表达。
PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells.
作者信息
Hsieh Meng-Hsun, Chen Yi-Ting, Chen You-Tzung, Lee Yi-Hsuan, Lu Jean, Chien Chung-Liang, Chen Hsin-Fu, Ho Hong-Nerng, Yu Chia-Jung, Wang Zhao-Qi, Teng Shu-Chun
机构信息
Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
出版信息
Nucleic Acids Res. 2017 Oct 13;45(18):10492-10503. doi: 10.1093/nar/gkx683.
Telomerase is highly expressed in cancer and embryonic stem cells (ESCs) and implicated in controlling genome integrity, cancer formation and stemness. Previous studies identified that Krüppel-like transcription factor 4 (KLF4) activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in ESCs. However, little is known about how KLF4 regulates TERT expression. Here, we discover poly(ADP-ribose) polymerase 1 (PARP1) as a novel KLF4-interacting partner. Knockdown of PARP1 reduces TERT expression and telomerase activity not only in cancer cells, but also in human and mouse ESCs. Recruitment of KLF4 to TERT promoter is reduced in PARP1-suppressed cells. The poly(ADP-ribose) polymerase activity is dispensable, while the oligo(ADP-ribose) polymerase activity is required for the PARP1- and KLF4-mediated TERT activation. Repression of Parp1 in mouse ESCs decreases expression of pluripotent markers and induces differentiation. These results suggest that PARP1 recruits KLF4 to activate telomerase expression and stem cell pluripotency, indicating a positive regulatory role of the PARP1-KLF4 complex in telomerase expression in cancer and stem cells.
端粒酶在癌症和胚胎干细胞（ESC）中高度表达，并与控制基因组完整性、癌症形成和干性有关。先前的研究表明，Krüppel样转录因子4（KLF4）激活端粒酶逆转录酶（TERT）的表达，并有助于维持ESC的自我更新。然而，关于KLF4如何调节TERT表达知之甚少。在这里，我们发现聚（ADP-核糖）聚合酶1（PARP1）是一种新的与KLF4相互作用的伙伴。敲低PARP1不仅会降低癌细胞中的TERT表达和端粒酶活性，也会降低人和小鼠ESC中的TERT表达和端粒酶活性。在PARP1抑制的细胞中，KLF4募集到TERT启动子的过程减少。聚（ADP-核糖）聚合酶活性是可有可无的，而PARP1和KLF4介导的TERT激活需要寡聚（ADP-核糖）聚合酶活性。在小鼠ESC中抑制Parp1会降低多能性标志物的表达并诱导分化。这些结果表明，PARP1募集KLF4以激活端粒酶表达和干细胞多能性，表明PARP1-KLF4复合物在癌症和干细胞中端粒酶表达中起正调控作用。
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