Cellular response to chromosomal aberrations
Elaborate mechanism are employed by each cell to faithfully propagate their genome and preserve a stable karyotype (constant number of chromosomes). In pathogenic situations however, loss or gains of chromosomes are often observed. These changes affect either a single chromosome (e.g. extra copy of chromosome 21 in Down syndrome) or a large number of chromosomes, which is frequently observed in cancer cells. Little is known about the impact of these chromosome gains or losses on cell physiology and how they promote the pathogenic state. In our laboratory we are using cutting-edge methodology to study the causes and consequences of karyotype changes.
Our Model System
To generate human cells carrying a single extra chromosome we use a technique called micronuclei mediated chromosome transfer (MMCT). To generate cells with extra copies of the whole sets of chromosomes (tetraploid cells) or with variable aneuploidy we treat the cells with drugs that interfere with cell division. Using state-of-the-art techniques including live cell imaging or flow cytometry we analyze how these cells propagate their abnormal genome. We also exploit genomics, transcriptomics and proteomics to determine the effects of the extra chromosomes on genome stability and protein homeostasis.
Impact of aneuploidy on genome stability
Using flow cytometry and live cell imaging we found that presence of extra chromosomes impairs proliferation of aneuploid cells. Global transcriptome and proteome analysis enabled identification of pathways that are deregulated in aneuploid cells irrespective of the identity of the extra chromosome. This analysis has revealed a strong down-regulation of DNA replication factors. Consistently, aneuploid cells show several hallmarks of replication stress. We are currently elucidating the mechanisms that contribute to replication stress in aneuploid cells.
Protein homeostasis in aneuploid cells
Cross-omic analysis by comparing genome, transciptome and proteome quantitative changes we found that genes from the extra chromosomes are normally transcribed and translated, but that expression levels of many proteins are adjusted to wild type levels. We study how autophagy, proteoasomal degradation or protein folding affect protein homeostasis in aneuploid cells and protein stability on a global scale.
Finding the Achilles heel of tetraploid cells
Sequencing of cancer genomes suggests that about 40 % of all cancers have undergone whole-genome doubling at some point during the tumorigenesis. In contrast, normally proliferating human cells rarely survive whole-genome doubling. Using RNAi and CRISPR/Cas9 we aim to determine factors that promote survival of tetraploid cell s in order to identify molecular targets that may be exploited for selective killing of cancers cells with abnormal karyotypes.
Want to find out more about Aneuploidy?
Check out the book “Aneuploidy in health and disease”