DNA damage-induced hepatocyte polyploidisation - how it happens and what are its consequences?

Formaldehyde is a genotoxic metabolite universally produced in our bodies at levels sufficient to cause irreversible DNA damage. This is usually prevented by (1) enzymatic detoxification and (2) DNA repair by the Fanconi Anaemia pathway. Mice lacking this two-tier protection accumulate widespread damage and have reduced lifespan. By studying tissue-specific responses in these mice, I discovered that formaldehyde is especially abundant in the liver and contributes to extensive polyploidisation of hepatocytes. This is also a feature of aged human hepatocytes. The purpose of this research is to discover the mechanisms that regulate DNA damage-induced polyploidisation and define its role in maintaining liver homeostasis. In the first instance I will understand how formaldehyde damages quiescent hepatocytes and forces them to re-enter the cell cycle. I will use hypothesis-driven approaches as well as in vivo CRISPR-Cas9 genetic screens to identify factors central to this process. By characterising aged mice with liver-specific deficiency in formaldehyde protection, I will uncover long-term consequences of polyploidisation and its impact on organ function. In the last part of this project, using different DNA repair-deficient mouse models I will aim to better understand the complex relation between genome stability, polyploidisation and liver cancer.