The consequences of aneuploidy in human cells

Aneuploidy is a change in number or structure of one or more
chromosomes that are not a multiple of the whole chromosome set.
One of the best known pathological aneuploidies is trisomy 21 (Down
syndrome), with chromosome 21 present in three instead of two
copies. Patients with Down syndrome display severe mental
retardation and growth defects. In fact, most abnormal aneuploid
karyotypes lead to spontaneous abortions during embryogenesis,
indicating that aneuploidy is not well tolerated in humans.
Aneuploidy was also shown to be a common hallmark of cancer
tissues; however, the debate is ongoing whether aneuploidy is
rather a by-product or a trigger of tumorigenesis. Even though
aneuploid karyotypes were already identified more than 100 years
ago little is understood about cellular physiology of aneuploidy
cells, especially in humans. To uncover the consequences of
numerical aneuploidy in human cells, I generated aneuploid cell
lines derived from the human cell lines HCT116 and RPE-1 hTERT.
First, we showed that aneuploid cells proliferate slower compared
to their disomic counterparts. A detailed cell cycle analysis
revealed that this delay was due to a prolonged G1 and S phase,
whereas G2 and M phase remained unperturbed. Furthermore, we
conducted an in depth genome wide comparison of DNA, mRNA and
protein levels in aneuploid cells. Using CGH, mRNA array and SILAC
technology, we quantified the changes in DNA, mRNA and protein
abundance. We revealed that extra chromosomes are actively
transcribed and translated. However, the abundance of some
proteins, particularly subunits of protein complexes and protein
kinases, are adjusted towards disomic levels. Additionally, we
asked how the cellular physiology is affected by the addition of a
specific chromosome. Two scenarios are possible: either the
cellular response depends on the additional chromosomes or all
aneuploid cells show the same changes of cellular physiology.
Indeed, we found that all aneuploid cell lines show similar
physiological responses, irrespective of the type of additional
chromosome. All aneuploid cell lines down-regulate DNA and RNA
metabolism and up-regulate among others energy metabolism, lysosome
function and membrane biosynthesis pathways. Lysosomes which are
involved in autophagy are besides the ubiquitin-proteasome system
important for cellular protein turn over. We found p62-dependent
selective autophagy increased in all analyzed cell lines with extra
chromosomes suggesting a role of p62-dependent selective autophagy
in maintenance of protein homeostasis upon expression of extra
protein in these cell lines.