Genomic instability as a driver of ageing 

DNA damage is a driver of aging. We study how ageing leads to a loss of coordination within the Base Excision repair pathway, which is essential for maintenance of genomic integrity in mitochondria and nuclear DNA. 

In ageing neurons, loss of coordination of Base Excision Repair leads to accumulation of half-repaired DNA molecules which might be more harmful than the original damage. We study the mechanisms of how Base Excision Repair in the nucleus and mitochondria affect aging neurons. We are also interested in how DNA repair can be modulated (pharmacologically and genetically) to promote healthy aging.

We use C. elegans as a model to study DNA repair across the lifespan. C. elegans expressing human alpha synuclein can be used to study how dopaminergic neurons are kept healthy during aging. Photo Fransisco Naranjo

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SMUG 1 at the intersection of RNA and DNA biology

Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. 

Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. 

We study this duality with particular attention to the SMUG1-DNA glycosylase, which is the main enzyme recognizing 5-hydroxymethyluracil, in RNA and DNA.

SMUG1 functions in Base Excision repair but also in processing, maturation and quality control of several types of RNA species. DOI: 10.3390/ijms241210307

Uracil Base Excision Repair in Cancer

The balance between enzymes that introduce modified bases and the enzymes that remove them generate the genetic variation that cancer cells can evolve from. We study the balance of APOBEC enzymes and Uracil-Base Excision Repair. We make mouse models to study how cancer develop and how these mechanisms might be exploited to kill cancer cells.