Waldron Joseph A, Jones Christopher I, Towler Benjamin P, Pashler Amy L, Grima Dominic P, Hebbes Stephen, Crossman Samuel H, Zabolotskaya Maria V, Newbury Sarah F
Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PS, UK.
Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PS, UK
Biol Open. 2015 Apr 2;4(5):649-60. doi: 10.1242/bio.201410199.
Programmed cell death, or apoptosis, is a highly conserved cellular process that is crucial for tissue homeostasis under normal development as well as environmental stress. Misregulation of apoptosis is linked to many developmental defects and diseases such as tumour formation, autoimmune diseases and neurological disorders. In this paper, we show a novel role for the exoribonuclease Pacman/Xrn1 in regulating apoptosis. Using Drosophila wing imaginal discs as a model system, we demonstrate that a null mutation in pacman results in small imaginal discs as well as lethality during pupation. Mutant wing discs show an increase in the number of cells undergoing apoptosis, especially in the wing pouch area. Compensatory proliferation also occurs in these mutant discs, but this is insufficient to compensate for the concurrent increase in apoptosis. The phenotypic effects of the pacman null mutation are rescued by a deletion that removes one copy of each of the pro-apoptotic genes reaper, hid and grim, demonstrating that pacman acts through this pathway. The null pacman mutation also results in a significant increase in the expression of the pro-apoptotic mRNAs, hid and reaper, with this increase mostly occurring at the post-transcriptional level, suggesting that Pacman normally targets these mRNAs for degradation. Our results uncover a novel function for the conserved exoribonuclease Pacman and suggest that this exoribonuclease is important in the regulation of apoptosis in other organisms.
程序性细胞死亡，即细胞凋亡，是一个高度保守的细胞过程，对于正常发育以及环境应激下的组织稳态至关重要。细胞凋亡的调控异常与许多发育缺陷和疾病相关，如肿瘤形成、自身免疫性疾病和神经紊乱。在本文中，我们展示了外切核糖核酸酶Pacman/Xrn1在调控细胞凋亡中的新作用。以果蝇翅成虫盘作为模型系统，我们证明Pacman基因的无效突变会导致成虫盘变小以及化蛹期致死。突变的翅成虫盘显示出凋亡细胞数量增加，尤其是在翅囊区域。这些突变盘也会发生代偿性增殖，但这不足以补偿同时增加的细胞凋亡。通过缺失每个促凋亡基因reaper、hid和grim的一个拷贝的缺失突变来挽救Pacman无效突变的表型效应，表明Pacman通过该途径发挥作用。Pacman无效突变还导致促凋亡mRNA hid和reaper的表达显著增加，这种增加主要发生在转录后水平，表明Pacman通常靶向这些mRNA进行降解。我们的结果揭示了保守的外切核糖核酸酶Pacman的新功能，并表明这种外切核糖核酸酶在其他生物体的细胞凋亡调控中很重要。
