Chromosome Instability, friend or foe: genetic and epigenetic causes in cancer

Abstract

Chromosome Instability (CI) compromises the fidelity of the transmission of the genetic material, and thus, is a grave risk for health. Many genetic diseases including cancer are characterised by CI. However, the leading causes identified so far can be different in each condition. Understanding the specific underlying mechanisms and how cells learn to deal with CI is of great relevance to design ad hoc and personalised therapeutic strategies. With this aim, we have been focused on three research lines: 1) investigating the involvement of DNA methylation in centromere stability and function, 2) unveiling a new player in chromosomal common fragile sites (CFSs) stability, 3) exploiting CI to induce senescence and allow cancer cells’ clearance. By using molecular and cell biology approaches, as well as microscopy techniques, we observed that global DNA methylation loss, a frequent event in cancer cells, undermines the correct loading of centromere proteins resulting in mitotic defects and CI. We also identified a key element, an helicase protein involved in the resolution of RNA:DNA hybrids at CFSs during mitosis, that appears to be critical for cancer cells’ survival. Moreover, we showed that curcumin treatment leads to senescence only tumor cells by increasing their endogenous CI. We also demonstrated that the combination of curcumin treatment and senolytic molecules is able to deplete cancer cells [1]. Our results pave the way for new therapeutic strategies against cancer progression that take advantage of the CI distinctive for each tumor context. We also set the course for DNA methylation essential to maintain centromere functionality and thus chromosomal stability.