Project number 16

Unraveling the molecular mechanisms underlying the mutagenic and carcinogenic effect of alcohol

1. Introduction
The risk of developing tumors of the oral cavity and oesophagus increases dramatically with increasing alcohol consumption. Although the causal link between ethanol (EtOH) intake and tumor formation is well-established, the precise toxic effects of EtOH are still not fully understood. Despite the medical relevance, very little is known about the molecular mechanisms that can be targeted therapeutically.
The carcinogenic effect of EtOH is thought to be due to acetaldehyde, which can form mutagenic DNA adducts. However, genome-wide assays suggest that the effects of EtOH are much broader. Moreover, a detailed characterization of the effects of EtOH on mammalian cells is lacking. A central hurdle is that measuring DNA damage and mutation rates is not trivial, especially in mammalian cells. In this project, we will therefore combine work in the model eukaryote Saccharomyces cerevisiae with work in mammalian cells.

2. Goals
1. Identify molecular mechanisms underlying mutagenic effect of EtOH with yeast deletion collection to identify key genes and pathways and knock-out mammalian cell lines to determine key components in higher eukaryotes.
2. Perform detailed characterization of effects of EtOH on mammalian cells:  RNA seq to identify processes affected by EtOH and exome seq to identify effects of EtOH on genome stability.
3. Determine mutational signature(s) of EtOH-related tumors
Techniques: standard and advanced molecular biology (in yeast and mammalian cell lines) and bioinformatics

3.  VIB labs
Work on yeast will be done in the Verstrepen group (molecular biology, systems biology, genome analysis - 50%), work in mammalian systems will be done in the Cools group (human genetics, exome and RNA seq - 50%), both at VIB-Leuven.

Keywords
cancer, mutagen, yeast, tumor, DNA damage

Supervisors
Jan Cools, VIB Center for the Biology of Disease, KU Leuven, Leuven
Kevin J. Verstrepen, VIB Lab of Systems Biology, KU Leuven, Leuven