ADP-ribosylation signaling in the DNA damage response
ADP-ribosylation (ADPr) is a biologically and clinically important post-translational modification (PTM) of proteins. Yet despite considerable efforts over the last decades, it has been difficult to investigate the mechanisms and functional consequences of this challenging PTM until recently.
With a first truly unbiased mapping of ADPr sites, we uncovered serine ADPr (Ser-ADPr) as a new type of histone mark (Leidecker et al. Nature Chemical Biology 2016) and described its biochemical basis by identifying its “writers” (Bonfiglio et al. Molecular Cell 2017) and “eraser” (Fontana et al. eLife 2017). We have also shown that upon DNA damage Ser-ADPr is the primary form of ADPr (Palazzo et al. eLife 2018), targeting hundreds of proteins (Molecular Cell 2017). Our discoveries have started a re-examination of 50 years of consensus understanding and have opened a large and novel research area into how ADPr regulates the DNA damage response, chromatin dynamics and transcription.
Currently, we are capitalizing on our lead to continue to push the frontiers of this long-overlooked PTM that is revolutionizing the research field. By combining our advanced proteomic methodology with biochemical and cellular approaches, we aim to understand at the molecular level how ADPr regulates DNA repair and the process of ageing.