Laudatio for Dr. Óscar Fernández-Capetillo
Presentation by Prof. Dr. Kai Simons, Dresden
“As we all know DNA plays a central role in our lives. It all starts with fertilization of the egg by one sperm followed by one cell division after the other that lead to the development of the embryo. The DNA is transcribed to give rise to the messenger RNAs that produce the specific protein set, characteristic of each cell. These processes are tightly regulated. Essential is that DNA integrity has to be maintained. This integrity is threatened from three sides. First, spontaneous reactions – mostly hydrolysis – cause deamination. Second, cellular metabolism generates reactive oxygen and nitrogen species and other metabolites that damage DNA. Third, DNA is under attack from exogeneous physical and chemical agents, such as radiation. The estimated number of breaks and base losses in nuclear DNA are as high as 105 lesions per day. DNA damage can induce mutations that give rise to cancer, cell death or contribute to aging.
To protect our DNA a complex and elaborate machinery has evolved. DNA injury generates a complex response involving more than 700 proteins. It is in this area of biology that our Eppendorf Award winner has been active. He has been analysing the impact of chromatin architecture on how to detect and repair of DNA breaks. One prime target of his research has been the histone variant, H2AX, which he has named the histone guardian of the genome. Histones are known to be involved as components of the fundamental repeating unit of the DNA, the nucleosome. The DNA is wrapped around a central core of eight histone protein subunits. The histones can be post-translationally modified by e.g. acetylation and these modifications lead to structural changes of the nucleosome that are instrumental in determining the transcription pattern of the cell. These post-translational modifications lead to epigenetic changes that are decisive for the phenotype of the cell and these can be transmitted from one cell to its progeny. The histone H2AX has a completely different function. It is involved in maintaining genomic stability. H2AX has been shown to mark the spot of DNA damage, specifically where double strand breaks have occurred. Following generation of a double strand break in the DNA, kinases are activated that leads to massive phosphorylation in the chromatin surrounding the DNA break. Our award winner has done pioneering work in characterizing the mechanisms involved in the H2AX repair cascade. He has focused on one of the key kinases involved, the ATR kinase. The H2AX histone is phosphorylated by the ATR kinase and then the phosphorylation cascade triggered by the kinase leads to a rush of proteins to the double strand break that engage in repairing the injury. This kinase is triggered to participate in repairing the damage, especially after UV irradiation. A single day on the beach can generate up to 105 UV photoproducts in each exposed keratinocyte in the skin!
Óscar Fernández-Capetillo has characterized the mechanisms of DNA repair and demonstrated that the phosphorylation marks on H2AX play a major role in focal assembly and retention of repair proteins in the chromatin regions near the damaged site and in the reorganization of chromatin structure. In his most recent research he has developed a fascinating mouse system for the study of the ATR kinase. By introducing an ATR kinase mutant into mice, found to be causative for the Seckel syndrome in humans, Óscar Fernández-Capetillo has for the first time produced an animal model for this disease. The Seckel syndrome is a human disorder characterized by intrauterine and postnatal growth retardation as well as profound microcephaly. Cells from these patients show defects in the ATR kinase – dependent DNA damage response. The Seckel syndrome demonstrates the essential role of the ATR kinase during normal embryogenesis. But another fascinating insight has been the discovery that these mice age very fast because of an accumulation of DNA damage during embryonic development. This could imply that if an embryo were exposed to DNA damage and replicative stress during development, the effects could determine how this individual will age in the future. The animal model for the Seckel syndrome also revealed that ATR kinase inhibition leads to killing of p53 deficient cells. The p53 protein is an important cancer suppressor and when inactivated malignant transformation is induced. Thus, the ATR kinase could be a novel drug target. The aim of his research group is now to find out how genome maintenance is safeguarded –particularly during replication- and to exploit this knowledge as a way to fight against cancer.
Oscar Fernandez-Capetillo (born in Bilbao, 1974) obtained his PhD from the University of The Basque Country working on the role of E2F transcription factors on the development of the immune system with Ana Zubiaga. He then joined the laboratory of André Nussenzweig at the National Cancer Institute, where he started his work on the cellular response to DNA damage, particularly focusing on the role of the histone variant H2AX and other chromatin-related aspects. After three years at the National Cancer Institute he was recruited to lead the Genomic Instability Group of the Spanish National Cancer Research Centre (CNIO). He recruited an active research around him at the CNIO and continued his pioneering work on chromatin, but has now mostly focused on developing cellular and animal tools for a study of the role of the ATR signalling cascade in the protection against cancer and ageing. His career has been recognized by several national and international awards and honours such as the EMBO Young Investigatorship (2008), an ERC Starting Grant (2007), the membership of the EPIGENOME Network of Excellence (2006) or the Swiss Bridge Award (2005).”