Bock Florian J, Tanzer Maria C, Haschka Manuel D, Krumschnabel Gerhard, Sohm Bénédicte, Goetsch Katrin, Kofler Reinhard, Villunger Andreas
Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
Sci Rep. 2015 Jun 11;5:11268. doi: 10.1038/srep11268.
The tumour suppressor p53 is an important mediator of cell cycle arrest and apoptosis in response to DNA damage, acting mainly by transcriptional regulation of specific target genes. The exact details how p53 modulates this decision on a molecular basis is still incompletely understood. One mechanism of regulation is acetylation of p53 on lysine K120 by the histone-acetyltransferase Tip60, resulting in preferential transcription of proapoptotic target genes. PDCD5, a protein with reported pro-apoptotic function, has recently been identified as regulator of Tip60-dependent p53-acetylation. In an effort to clarify the role of PDCD5 upon DNA damage, we generated cell lines in which PDCD5 expression was conditionally ablated by shRNAs and investigated their response to genotoxic stress. Surprisingly, we failed to note a rate-limiting role of PDCD5 in the DNA damage response. PDCD5 was dispensable for DNA damage induced apoptosis and cell cycle arrest and we observed no significant changes in p53 target gene transcription. While we were able to confirm interaction of PDCD5 with p53, we failed to do so for Tip60. Altogether, our results suggest a role of PDCD5 in the regulation of p53 function but unrelated to cell cycle arrest or apoptosis, at least in the cell types investigated.
肿瘤抑制因子p53是细胞周期阻滞和凋亡的重要介导因子，可响应DNA损伤，主要通过对特定靶基因的转录调控发挥作用。p53如何在分子水平上调节这一决定的具体细节仍未完全了解。一种调控机制是组蛋白乙酰转移酶Tip60使p53的赖氨酸K120乙酰化，从而导致促凋亡靶基因的优先转录。PDCD5是一种具有促凋亡功能的蛋白质，最近被确定为Tip60依赖性p53乙酰化的调节因子。为了阐明PDCD5在DNA损伤中的作用，我们构建了通过短发夹RNA（shRNA）条件性敲除PDCD5表达的细胞系，并研究了它们对基因毒性应激的反应。令人惊讶的是，我们未发现PDCD5在DNA损伤反应中具有限速作用。PDCD5对于DNA损伤诱导的凋亡和细胞周期阻滞是可有可无的，并且我们未观察到p53靶基因转录有显著变化。虽然我们能够证实PDCD5与p53之间存在相互作用，但未证实其与Tip60之间存在相互作用。总之，我们的结果表明PDCD5在p53功能调控中发挥作用，但至少在所研究的细胞类型中与细胞周期阻滞或凋亡无关。
