Quevedo Oliver, Ramos-Pérez Cristina, Petes Thomas D, Machín Félix
Unidad de Investigación, Hospital Universitario Nuestra Señora de la Candelaria, 38010 Santa Cruz de Tenerife, Spain.
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710
Genetics. 2015 Jul;200(3):755-69. doi: 10.1534/genetics.115.177626. Epub 2015 May 12.
Genomic instability is a common feature found in cancer cells . Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanisms that explain cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient loss yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes, and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity, are detected mainly on the ribosomal DNA-bearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins, and controlling spindle dynamics in a well-defined window within anaphase, we speculate that the transient loss of Cdc14 activity causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny.
基因组不稳定是癌细胞的一个常见特征。因此,在常见癌症综合征中鉴定出的许多肿瘤抑制基因都参与了在每次细胞分裂过程中维持基因组的稳定性,通常被称为基因组守护者。基因组守护者的失活突变和表观遗传沉默被认为是解释癌症相关基因组不稳定的最重要机制。然而,对于基因组守护者蛋白的瞬时失活是否会引发基因组不稳定,以及如果会引发,会发生何种类型的不稳定,我们却知之甚少。在这项研究中,我们发现,在模式生物酿酒酵母中,关键磷酸酶Cdc14仅在一个细胞周期内发生短暂且可逆的失活,就足以导致二倍体细胞出现多个严重的染色体重排和倍性变化。有趣的是,我们观察到这种瞬时缺失产生了一种特征性的指纹图谱,即三体往往出现在小尺寸染色体上,而主要在携带核糖体DNA的第十二号染色体上检测到通常与杂合性同时丧失相关的严重染色体重排。考虑到Cdc14在防止后期桥形成、重置复制起点以及在后期的一个明确窗口内控制纺锤体动力学方面的关键作用,我们推测Cdc14活性的瞬时丧失会导致细胞经历一次单一的有丝分裂灾难,对后代的基因组稳定性产生不可逆转的影响。