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. My PhD, funded by an FPU fellowship, was awarded in 2009 with ‘Sobresaliente Cum Laude’, European Mention, and later on awarded with the ‘Premio Extraordinario de Doctorado’. I development 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 co-transcriptional R-loops impair replication fork progression and identified that as the main cause of transcription-associated genetic instability. I further showed that the phenotypes of THO mutants could be observed genome-wide. 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 then decided to deepen my understanding of the replication process with a leading scientist in the field, Dr. John Diffley. For this purpose, I moved to UK in 2010 and worked at Clare Hall Laboratories (belonging to CRUK until April 2015 and to The Francis Crick Institute since then), where I was funded by a long-term EMBO Fellowship and by CRUK to work on 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. Thanks to a grant from the AECC, I was back to Spain in 2015, where I continued my interest in the role of chromatin in recombination at forks. We recently reported that Rpd3L and Hda1 histone deacetylases are essential for the repair of broken forks, and we are currently pursuing this work by the use of histone deacetylases inhibitors in human cell cultures.
I have also contributed to identify new genes involved in the prevention or resolution of R-loops in yeast and human cells. In parallel, I work on the causes and consequences of R-loop accumulation on human cells deficient in the tumor suppressor gene BRCA2 with the aim of understanding the molecular basis of tumorigenesis. Altogether my research lines focus on the role of chromatin, and in particular histone acetylation, in the repair of replication-induced damage and in transcription-replication conflicts in yeast and human cells.