Main Research lines
- Transcription-associated genetic instability and R-loops
- Mechanisms preventing irreversible replication fork arrest
- Functions of histone deacetylases at replication forks
Main Research lines
My research interests have focused on transcription and replication as main sources of genetic instability. During my PhD, I worked with Prof. Andrés Aguilera on transcription, and R-loops in particular, as a source of genetic instability. I developed powerful genetic tools for the identification of R-loops in vivo by the heterologous over-expression of human AID in yeast mutants of the THO complex, involved in mRNP biogenesis. I also contributed to show that the ubiquitous accumulation of co-transcriptional R-loops impair replication fork progression and identified that as a major cause of transcription-associated genetic instability. In agreement with R-loops being a frequent source of DNA damage, I showed that to survive replication stress, THO mutants require a functional S-phase checkpoint, known to be essential for the maintenance of replication fork stability.
I moved to UK in 2010 to work in the laboratory of Dr. John Diffley at Clare Hall Laboratories (belonging to CRUK until April 2015 and to The Francis Crick Institute since then), where I studied the role of S-phase checkpoints in replication fork stabilization. The combination of whole-genome sequencing technics with classic genetics allowed me to describe that the Rpd3L histone deacetylase complex is responsible for the DNA damage sensitivity of checkpoint mutants. I then searched for the essential factors involved in fork destabilization in yeast and human cells, uncovering an unexpected link with recombination. Back to Spain in 2015, I continued my interest in the role of chromatin in recombination at forks. I also contributed to identify new genes involved in the prevention or resolution of R-loops in yeast and human cells and explored the causes of DNA-RNA hybrid accumulation in human cells deficient in the tumor suppressor gene BRCA2. Altogether my research lines include the study of causes and consequences of replication fork damage focusing on the role of chromatin, and in particular histone acetylation, in the repair of replication-induced damage, in transcription-replication conflicts and in the mechanisms preventing irreversible arrest in yeast and human cells.