Ghamrasni S El, Cardoso R, Li L, Guturi K K N, Bjerregaard V A, Liu Y, Venkatesan S, Hande M P, Henderson J T, Sanchez O, Hickson I D, Hakem A, Hakem R
Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Ageing, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
Oncogene. 2016 Sep 15;35(37):4836-45. doi: 10.1038/onc.2016.16. Epub 2016 Feb 15.
Rad54 and Mus81 mammalian proteins physically interact and are important for the homologous recombination DNA repair pathway; however, their functional interactions in vivo are poorly defined. Here, we show that combinatorial loss of Rad54 and Mus81 results in hypersensitivity to DNA-damaging agents, defects on both the homologous recombination and non-homologous DNA end joining repair pathways and reduced fertility. We also observed that while Mus81 deficiency diminished the cleavage of common fragile sites, very strikingly, Rad54 loss impaired this cleavage to even a greater extent. The inefficient repair of DNA double-strand breaks (DSBs) in Rad54(-/-)Mus81(-/-) cells was accompanied by elevated levels of chromosome missegregation and cell death. Perhaps as a consequence, tumor incidence in Rad54(-/-)Mus81(-/-) mice remained comparable to that in Mus81(-/-) mice. Our study highlights the importance of the cooperation between Rad54 and Mus81 for mediating DNA DSB repair and restraining chromosome missegregation.
Rad54和Mus81哺乳动物蛋白存在物理相互作用，对同源重组DNA修复途径很重要；然而，它们在体内的功能相互作用尚不清楚。在这里，我们表明Rad54和Mus81的联合缺失导致对DNA损伤剂敏感、同源重组和非同源DNA末端连接修复途径均出现缺陷以及生育力降低。我们还观察到，虽然Mus81缺陷减少了常见脆性位点的切割，但非常显著的是，Rad54缺失对这种切割的损害更大。Rad54(-/-)Mus81(-/-)细胞中DNA双链断裂（DSB）修复效率低下伴随着染色体错分离和细胞死亡水平的升高。也许因此，Rad54(-/-)Mus81(-/-)小鼠的肿瘤发生率与Mus81(-/-)小鼠相当。我们的研究强调了Rad54和Mus81之间合作对于介导DNA DSB修复和抑制染色体错分离的重要性。
