The BRCT domain enhances DNA binding and catalytic efficiency of fungal PARPs

Abstract Aspergillus fumigatus infections are a major yet often neglected global health challenge magnified by a growing at-risk population, limited treatment options, and the emergence of drug-resistant strains. Regulation of the DNA damage response (DDR) by ADP-ribosylation signalling has recently emerged as an important feature of fungal pathogenesis, but the underlying mechanisms remain largely elusive. Here we present a comprehensive phylogenetic and functional characterisation of Af -PARP1, the A. fumigatus PARP homologue. Our data reveal Af -PARP1 as a DNA-dependent poly(ADP-ribosyl)transferase with unique domain architecture, DNA damage selectivity, and activation dynamics distinct from its mammalian and plant homologues. We show that the fungal specific BRCT domain plays a crucial role in both damage recognition and ADP-ribosylation signal establishment. Collectively, our findings reveal a divergence in DDR-associated ADP-ribosylation specific to fungi, highlighting the potential of this signalling pathway as target for antifungal therapy.