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Discovery and development of Serine ADP-ribosylation

Discovery and development of Serine ADP-ribosylation

; Max Planck 鶹Ƶ for Biology of Ageing

Ivan Matić studied Pharmaceutical Biotechnology at the University of Bologna and completed his PhD at the Max Planck 鶹Ƶ of Biochemistry under the supervision of Matthias Mann. From 2010, he was a Sir Henry Wellcome Postdoctoral Fellow at the University of Dundee, before establishing his own research group at the Max Planck 鶹Ƶ for Biology of Ageing in 2014. Dr. Matić was selected as an EMBO Young Investigator in 2018 and holds an ERC Consolidator Grant. The Matić group develops proteomics and chemical biology technologies for the analysis of ADP-ribosylation, a post-translational modification that has been a challenging frontier for over 60 years. They apply these methodologies to elucidate the molecular mechanisms of key signaling pathways relevant to the DNA damage response, chromatin dynamics and aging.

ADP-ribosylation (ADPr) is a widespread and versatile PTM that targets proteins, RNA, and DNA, regulating vital cellular pathways across all kingdoms of life - from bacterial pathogenesis to cancer, immunity, and aging. It is primarily recognized for its role in the DNA damage response and the clinical importance of PARP inhibitors, ‘blockbuster’ drugs used in cancer therapy. However, ADPr signaling pathways have remained highly understudied due to decades of persistent challenges. Employing the first unbiased proteomics approach for ADPr, we identified Serine ADPr as a novel histone modification. This led to our discovery that the HPF1/PARP1 complex isthe writer of this novel PTM, representing a new paradigm for PARP1 signaling. We then transformed these fundamental discoveries into a broadly applicable technology. Building on our insights into the crosstalk between histone marks, we developed a phospho-guided approach that served as the foundation for generating the first site-specific ADPr antibodies, a milestone that had eluded researchers for over fifty years. Our novel ability to explore mono-ADPr with unmatched specificity and sensitivity enabled us to introduce the concept ofmono-ADPr as a second wave of PARP1 signaling. Recently, we have further extended the reach of our tools toward previously elusiveAsp/Glu-ADPr by establishing general approaches for preserving ester-linked PTMs, which also encompass emerging unconventional ubiquitination. These new concepts and tools are fostering discoveries in laboratories worldwide, not only within the context of the DNA damage response and chromatin dynamics, but also extending to a range of biological processes, from aging to immunity.

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