How homologous recombination (HR), the major error-free pathway for DNA repair in mammalian cells, regulates telomeres and acts to prevent genomic instability, the underlying mechanism of many cancers.
Genome instability is a hallmark of human tumours. DNA mutations and genome rearrangements are in almost all cases responsible for the aberrant proliferation and metastatic behaviour of cancer cells. Work in Dr. Madalena Tarsounas’ laboratory aims to understand the causes of genome instability and the cellular mechanisms responding to it. This will not only enhance possibilities of cancer prevention, but also the development of treatment modalities that exploit the DNA damage tolerance of cancer cells.
Telomeres are structures at chromosome ends, consisting of repetitive DNA sequences and associated proteins. They protect chromosome ends from degradation and fusion, both of which cause genome instability similar to unrepaired DNA double-strand breaks. Telomere dysfunction is often associated with the onset of tumorigenesis. The work in Dr. Tarsounas laboratory investigates how factors involved in DNA repair by homologous recombination contribute to the establishment of protective telomeric structures and how they facilitate the successful completion of telomere replication. An important aspect of this work is understanding the DNA damage response emanating from unprotected or damaged telomeres. These studies are extended to analyse how components of the shelterin telomeric complex contribute to telomere protection and tumour suppression.
Another major line of investigation in Dr. Tarsounas laboratory is the action of homologous recombination proteins at sites of ionizing radiation-induced DNA damage. A group of five essential homologous recombination factors, the RAD51 paralogs, is currently under investigation. These form complexes with each other to promote DNA double strand break repair, however their mechanism of action is still poorly understood. Previous work in the Tarsounas laboratory has shown that a key role of at least two of the RAD51 paralogs, RAD51C and XRCC3, is to mediate the generation of a DNA damage signal at break sites, required for the appropriate cellular response to damage. The study of the role of RAD51C/XRCC3 at break sites will help our understanding how DNA damage sites are efficiently recognised, possibly by remodelling the chromatin landscape surrounding DNA breaks. This work will also investigate how the other RAD51 paralog family members function at DNA breaks, both in the early steps of initiating homologous recombination reactions, as well as during subsequent steps that complete the repair process.
Nov 2011 Senior Group Leader, The CR-UK/MRC Gray Institute for Radiation, Oncology and Biology, University of Oxford
Dec. 2005 Group Leader, The CR-UK/MRC Gray Institute for Radiation, Oncology and Biology, University of Oxford
1999-2005 Postdoctoral Fellow, Cancer Research UK , Clare Hall Laboratories