Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells.

Angela Lauriola,Tommaso Zanocco-Marani,Domenico D’Arca,Andrea Martello,Andrea Caporali,Gaetano Marverti,Daniele Guardavaccaro,Pierpaola Davalli,Sebastian Fantini,Sabine Mai

doi:10.3390/cancers12040993

Abstract

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.

Highlights

Genome integrity is continuously threatened by DNA lesions resulting from both endogenous and exogenous stress that causes genome damage and, genomic instability
Vein Endothelial Cells (HUVEC) was observed (Figure S2B). These findings suggest that the spindle assembly checkpoint (SAC), a surveillance mechanism that ensures the fidelity of chromosomal segregation during mitosis, might be defective in TpMs-depleted HCT116 cells
Our results indicate that the silencing of TpMs expression leads to chromosome mis-segregation, structural/numerical chromosomes aberrations (Figures 1 and 2) as well as DNA

Summary

Introduction

Genome integrity is continuously threatened by DNA lesions resulting from both endogenous and exogenous stress that causes genome damage and, genomic instability. Eukaryotic cells are endowed with interrelated pathways that face DNA damage, allowing DNA repair and correct cell cycle progression. This defensive system is comprehensively known as DNA damage response (DDR). DNA repair and cell cycle control are deeply related, as the correct duplication and transmission of genetic material are the main objectives of the cell division process [1]. The proper conditions for cell division are set during the cell cycle thanks to the action of multiple checkpoints.

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Conclusion