Centromeric instability in human cells undergoing immortalization

Abstract

Chromosomal instability is an important pathway for cells to generate new chromosome aberrations, which may contribute to carcinogenesis. Of various forms of chromosomal instability, centromeric instability remains particularly poorly understood. In the present study, we found that centromeric instability, evidenced by dynamic formation of centromeric or pericentromeric rearrangements, breaks, deletions or iso-chromosomes, was a general phenomenon in human cells undergoing immortalization by various methods, including expressions of human papillomavirus oncogenes (HPV 16-E6E7), human telomerase reverse transcriptase (hTERT) plus HPV 16-E6E7, and hTERT accompanied by p16INK4a inactivation. In particular, centromeric instability cooperated with telomeric instability in pre-immortal HPV 16-E6E7-expressing cells. This was evidenced by: (1) the progressive formation of centromeric deletions or rearrangements on specific chromosomes carrying critically short (signal-free) telomeres in cell lines of different epithelial cell types expressing HPV16-E6E7, suggesting that centromeric or pericentromeric regions were fragile and prone to be broken after chromosomal end-to-end fusions; and (2) preferential fusions between centromeric and telomeric ends of chromosomes with critically short telomeres. Since HPV16-E6 and E7 inactivate p53 and RB proteins, respectively, and most human cancers have p53 and RB pathway defects, the cell systems are relevant to cancer. Considering that cellular immortalization is a prerequisite for cancer initiation, our results suggest that centromeric instability might play an important role in the early process of cancer development.