Allosteric activation of PARP2 self-PARylation by SUMO constrains DNA-break-dependent catalytic functions

Poly(ADP-ribose) polymerase 2 (PARP2) is a key player in sensing DNA breaks and initiating DNA damage repair by catalyzing the transfer of ADP-ribose units from NAD⁺ to target proteins, a process known as Poly(ADP-ribosyl)ation (PARylation). Post-translational modifications (PTMs), such as phosphorylation, ubiquitylation, SUMOylation, and PARylation are intricately linked to the DNA damage response (DDR) and repair. However, modulation of the catalytic and noncatalytic activities of these enzymes through physical interactions with PTMs and enzymes regulates DNA damage detection, DDR, and DNA repair. Specifically, SUMOylation plays a vital role in DDR and DNA repair through covalent modification and noncovalent interactions. Here, we report that small ubiquitin-like modifier (SUMO) binds human PARP2 through noncovalent interactions, predominantly mediated by the N-terminal region (NTR) of PARP2. Surprisingly, SUMO stimulated PARP2 self-PARylation activity but hampered the DNA-dependent stimulation. Furthermore, competition binding studies suggest that SUMO binding promotes DNA release from PARP2. Together, our work uncovers a novel mechanism of SUMO-mediated allosteric regulation of PARP2 function, providing new insights into the possible interplay between SUMOylation and PARylation in DDR and DNA repair.