ADP-ribosylation is a fundamental protein modification that plays key roles in a range of processes related to ageing and ageing-related diseases, starting with the maintenance of genome stability and in the context of NAD+ metabolism.
Proteins, the workhorses of cellular life, play critical and diverse roles in virtually every cellular process. Post-Translational Modifications (PTMs) are chemical modifications that occur to proteins after synthesis to greatly expand their functional diversity in space and time. ADP-ribosylation (ADPr) is a widespread and versatile PTM that regulates many physiological and pathological processes across all kingdoms of life, from the DNA damage response and cancer to neurological disorders and aging. ADPr has also received considerable attention in the last few years because of the clinical significance of PARP inhibitors as blockbuster cancer therapy drugs. Despite the clear biological and clinical importance of ADPr, it has been very challenging to study this chemically complex PTM at the molecular level.
We have converted our fundamental discoveries of serine ADP-ribosylation by the HPF1/PARP1 writer complex and the interplay of histone marks into a foundational chemical biology technology for elucidating aging-related signaling pathways at the molecular level.
Our research program aims to elucidate the molecular mechanisms of DNA repair and aging by investigating the role of ADP-ribosylation (ADPr) in these biological processes.
Our seminal identification of serine ADPr as a new type of histone mark and of the HPF1/PARP1 complex as its writer (Leidecker et al. Nature Chem Bio 2016; Bonfiglio et al. Mol Cell 2017) represents a paradigmatic shift in the understanding of PARP1 signaling. More recently, we have converted these fundamental biological discoveries into a foundational technology to elucidate the prevalence of mono-ADPr upon DNA damage (Bonfiglio et al. Cell 2020).
Our innovative tools, which are already used in many laboratories worldwide, have unlocked the ability to explore all forms of mono-ADPr, the long-elusive primary outcome of the vast majority of ADPr writers. Further improvements in our methodology have enabled us to elucidate the DNA damage-induced mono-ADPr as a second wave of PARP1 signaling (Longarini et al. Molecular Cell 2023).
Against this backdrop, we are now focusing on three main topics: