1. Genomic instability as a major driving force of tumorigenesis

Cancer development is a complex multi-step process, involving a wide network of cellular events. Genomic instability, a hallmark of cancer, enables the acquirement of new characteristics required for tumorigenesis. We focus on the different cellular pathways which are altered under aberrant oncogene expression, causing various cellular stress reactions leading to perturbed DNA replication dynamics and chromosomal instability. We have shown that aberrant oncogene over-expression forces DNA replication to proceed under suboptimal conditions such as nucleotide deficiency, leading to replication stress and DNA damage (Bester et al. Cell 2011). Recently, we have demonstrated that activation of the RAS oncogene perturbs DNA replication due to increased topoisomerase 1 expression, disturbing the regulation of R-loop homeostasis and resulting in genomic instability (Sarni et al. Cell Reports 2022).

Another aspect of our work focuses on the tumor suppressor gene TP53, known as the “guardian of the genome” as it plays a key role in restricting tumor initiation and progression. We study the mechanisms underlying genomic instability including the catastrophic chromothripsis instability event, associated with aggressive tumorigenesis in cells deficient for wild type p53. We found that p53 loss leads to replication stress resulting in genomic instability. We found that nucleotide supplementation rescues replication stress, DNA damage and proliferation crisis (in progress).

Altogether, unfolding the molecular basis underling genome instability in cancer may open new potential prevention and therapeutic approaches. 

A mismatch between proliferation and metabolite production may characterize oncogenic cell cycles (Venkitaraman 2011, Preview in Cell on Bester et al., Cell 2011).