Luciano Di Croce

Centre de Regulació Genòmica

Using embryonic stem cells from mice, we found that the enzyme Thymine DNA Glycosylase (TDG) is critical for cell differentiation. They observed that TDG levels fluctuate as part of the cell’s normal routine. When the cell is preparing to divide, TDG levels are high, but they drop off once the cell enters the division phase.

Temporarily altering TDG levels also changed the way stem cells differentiate, or turn into different types of cells. For example, stem cells with tweaked TDG levels had an increased tendency to turn into heart muscle cells. This suggests that the starting amount of TDG in pluripotent cells can affect what type of cells they become when they differentiate.

One of the surprising findings is that TDG mainly interacts with p53, a well- known tumour suppressor. The p53 gene is one of the most frequently mutated genes in human cancers, with around half of all human tumors containing a mutation or deletion in the gene.

We found that TDG works by facilitating p53’s chromatin recruitment, effectively controlling the p53 transcriptional response in a cell cycle-dependent manner.

This regulation was pivotal for cell fate decisions during differentiation from pluripotency.

Cancer is a common disease caused by problems in cell fate decision-making. When the processes that control cell growth, differentiation, and death are disrupted, cells may proliferate uncontrollably, fail to differentiate into their intended cell types, or refuse to die when they should, all of which contribute to the development and progression of the disease.

While further work is needed to explore TDG’s exact role in cancer, this study could open up new avenues for investigating the molecular mechanisms behind cancer development, which could eventually lead to new diagnostic and therapeutic strategies.