[SCItalk] The control of histone and nucleotide availability in neurodevelopment and cancer therapy
Institute for Research in Biomedicine (IRB Barcelona), Spain
The DNA damage response (DDR) is a signaling network that identifies DNA lesions and orchestrates diverse cellular responses. Defects in the DDR lead to the accumulation of genomic instability and underlie human disorders characterized by different combinations of neurodevelopmental defects, immunodeficiency, infertility and cancer predisposition. DNA replication represents a major source of endogenous DNA damage and replication stress, the stalling of DNA replication forks, has been implicated in the pathology of neurodevelopmental disorders, such as Seckel Syndrome, and has been proposed to be a targetable vulnerability of cancer cells. We have identified the Tousled like kinases 1 and 2 (TLK1 and TLK2), that are regulated by the DDR, as suppressors of replication stress through their promotion of histone supply via regulation of the ASF1 histone chaperones. I will discuss current data and the potential roles of TLK1 and TLK2 in neurodevelopment and cancer therapy. In addition, I will present new work on ADSL, a key component of the de novo purine nucleotide synthesis pathway. ADSL deficiency underlies a severe neurodevelopmental disorder (ADSLD) and we have identified several unexpected cellular defects in ADSL depleted cells that influence neurodevelopment in animal models and suggest potential therapeutic interventions using existing anticancer agents.
Travis H. Stracker joined the IRB Barcelona as a Principal Investigator in the Cancer Science program in 2009. He obtained his B.S. in Genetics at the University of Georgia, Athens, GA, USA, in 1996 and his Ph.D. in Biology in the lab of Matthew D. Weitzman at the Salk Institute for Biological Studies and the University of California, San Diego, CA, USA, in 2002. From 2003 to 2009, he was a Research Associate in the lab of John H.J. Petrini at Sloan-Kettering Institute for Cancer Research in New York City, NY, USA. The primary goals of Dr. Stracker’s lab are to understand the role of genomic instability in human disease and to leverage knowledge of the DNA damage response (DDR) to identify new targets for cancer therapy. To these ends, his lab uses an array of both cellular and organismal models to explore the molecular and organismal functions of proteins linked to the DDR. His current work is focused on the Tousled like kinases 1 and 2 (TLK1 and TLK2) that control histone supply and are regulated by the DDR. They have defined key roles for the TLKs in suppressing replication stress and innate immunity and are exploring their potential as anticancer targets. In addition, they are analyzing the roles of the TLKs in vivo, as TLK2 mutations have been recently linked to a distinct neurodevelopmental disorder characterized by microcephaly and autism spectrum disorder.
Host: Julián Cerón - Modeling human diseases in C. elegans group