At the crossroads of ADP-ribose, PARP1, and XRCC1 in the genotoxic stress response

Abstract

ADP-ribosylation is ADP-ribosylation is an essential post-translational modification that plays key roles in a multitude of (patho-) physiological processes and is, among others, catalysed by members of the poly(ADP-ribose) polymerase (PARP) family. PARPs use nicotinamide adenine dinucleotide (NAD+) as a substrate to attach ADP-ribose moieties to target molecules, ranging from DNA and RNA to a vast number of proteins that can be modified at various amino acids. Modifications can either consist of a single ADP-ribose unit (i.e. mono-ADP-ribosylation, MARylation) or extend up to 200 units in length, adopting linear and/or branched conformations (i.e. poly(ADP-ribosyl)ation, PARylation). Besides covalent modification, proteins can also non-covalently interact with PAR chains through various PAR reader modules. Collectively, ADP-ribosylation is a highly diverse modification and its dynamic is not only contingent on PAR formation, but also on various catabolising enzymes that swiftly remove ADP-ribose moieties or PAR chains from target molecules. Although PARylation has been extensively studied in recent years, several open questions remain, and the overall goal of this thesis was to further elucidate the biological significance of PAR structural diversity, the interplay between the two important DNA repair factors PARP1 and XRCC1, and finally the interplay between the main PAR catabolising enzymes PARG and ARH3.