Moreover, our in vitro measured errors of human DNA Pol ε show remarkable similarity to mutations of patients deficient in Pol ε repair, explaining (among others) the mutational signature 14. 9/

What did we find? That human DNA polymerase ε does indeed make frequent errors when replicating CpGs! Especially methylated ones. When not repaired, this causes CpG>TpG mutations. 8/

To test this, we needed to develop a new technique, Polymerase Error Sequencing (PER-seq), to measure errors made by a given polymerase. I vividly remember how someone said in that meeting “This should be fairly easy, we should have it done in three months…” 6/

Is it possible that replication errors frequently create CpG>TpG mutations? Independently of deamination!

We published the cancer patient data analysis supporting this crazy hypothesis in DNA Repair www.sciencedirect.com/science/arti...
5/

However, about 9 years ago, we noticed that patients deficient in repair of replication errors have a huge number of CpG>TpG mutations. How is this possible, if CpG>TpG were coming from spontaneous deamination? 🤔 4/

Cytosines in the CpG context are mostly in the form of 5-methylcytosine. This epigenetic modification is important for gene regulation, but it can also spontaneously deaminate, creating a thymine. This results in a CpG>TpG mutation. 3/

C to T mutations in CpGs are more than 10 times more frequent than any other mutation type. They are present in most of our cells, across different tissues, and contribute to cancer, genetic diseases, and evolution. It was thought to be pretty well understood what causes them. 2/

We are recruiting! Senior postdoc in computational cancer genomics/epigenomics @ludwigcancer.bsky.social @ox.ac.uk. Lead research into epigenetic drivers of secondary AML with rich omics data + strong clinical/wet-lab collaborations.
cutt.cx/YUoB
We look forward hearing from you!

#epigenetics #jobs