Lauriola Angela, Martello Andrea, Fantini Sebastian, Marverti Gaetano, Zanocco-Marani Tommaso, Davalli Pierpaola, Guardavaccaro Daniele, Mai Sabine, Caporali Andrea, D'Arca Domenico
Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Department of Biotechnology, University of Verona, 37134 Verona, Italy.
Cancers (Basel). 2020 Apr 17;12(4):993. doi: 10.3390/cancers12040993.
Mitotic perturbations frequently lead to chromosome mis-segregation that generates genome instability, thereby triggering tumor onset and/or progression. Error-free mitosis depends on fidelity-monitoring systems that ensure the temporal and spatial coordination of chromosome segregation. Recent investigations are focused on mitotic DNA damage response (DDR) and chromosome mis-segregations with the aim of developing more efficient anti-cancer therapies. We previously demonstrated that trichoplein keratin filament binding protein (TpMs) exhibits hallmarks of a tumor suppressor gene in cancer-derived cells and human tumors. Here, we show that silencing of TpMs expression results in chromosome mis-segregation, DNA damage and chromosomal instability. TpMs interacts with Mad2, and TpMs depletion results in decreased levels of Mad2 and Cyclin B1 proteins. All the genetic alterations observed are consistent with both defective activation of the spindle assembly checkpoint and mitotic progression. Thus, low levels of TpMs found in certain human tumors may contribute to cellular transformation by promoting genomic instability.
有丝分裂扰动常常导致染色体错分离，进而产生基因组不稳定，从而引发肿瘤的发生和/或进展。无误的有丝分裂依赖于确保染色体分离的时间和空间协调的保真度监测系统。最近的研究集中在有丝分裂DNA损伤反应（DDR）和染色体错分离上，旨在开发更有效的抗癌疗法。我们之前证明，毛透明蛋白角蛋白丝结合蛋白（TpMs）在癌症衍生细胞和人类肿瘤中表现出肿瘤抑制基因的特征。在这里，我们表明TpMs表达的沉默会导致染色体错分离、DNA损伤和染色体不稳定。TpMs与Mad2相互作用，TpMs的缺失导致Mad2和细胞周期蛋白B1蛋白水平降低。观察到的所有基因改变都与纺锤体组装检查点的缺陷激活和有丝分裂进程一致。因此，在某些人类肿瘤中发现的低水平TpMs可能通过促进基因组不稳定而导致细胞转化。
