PARP2 Catalytic Activity Is Allosterically Stimulated by Binding to the c-KIT1 G-Quadruplex

Abstract

PARP2, along with PARP1, is involved in the maintenance of the genomic stability. PARP2 catalyzes the formation of poly(ADP-ribose) to recruit repair proteins at the site of DNA breaks. Single-strand (SSB) and double-strand (DSB) DNA breaks are bona fide stimulators of PARP2 catalytic activity. However, the regulation of PARP2 catalytic activity by G-quadruplex DNA structures, abundant in regulatory and promoter regions of proto-oncogene and telomeres, has not been studied. Here, we report that PARP2 binds to the proto-oncogene-specific parallel G-quadruplex, c-KIT1-G4. c-KIT1-G4 stimulates the catalytic activity of PARP2. However, the c-KIT1-G4-dependent stimulation of PARP2 catalytic activity is 2-fold lesser than 5′P-SSB DNA, a cognate stimulator of PARP2 catalytic activity. The N-terminal region of PARP2 is dispensable for c-KIT1-G4 DNA-dependent self-PARylation catalytic activity but contributes to the c-KIT1-G4 DNA binding affinity of PARP2 along with the WGR domain. Altogether, our work reveals that PARP2 selectively binds to a higher-order DNA structure and is allosterically activated.