Extended Data Fig. 10: Mutations that cause resistance to PARP inhibitors.

a, Linker histone H1 is accessible for PARylation while bound to chromatin. Superposition of cryo-EM models of H1-bound nucleosome (grey; PDB 5NL0) and PARP2–HPF1–nucleosome shows that both complexes can be bound simultaneously to the nucleosome. b, Model of DNA break recognition by PARP enzymes. Environmental sources and errors in DNA processing enzymes can result in DNA breaks. Poly-ADP ribosylation, a post-translation modification deposited by PARP family of enzymes, is the signalling molecule for DNA repair. PARP2 will bind DNA breaks and bridge the two broken ends. This changes the conformation of the autoinhibitory HD subdomain and activates the enzyme to ADP-ribosylate histones. ADP-ribosylation recruits subsequent proteins involved in DNA repair, while PARP–HPF1 remains bound to chromatin. A further increase in PARP automodification releases the complex from chromatin, handing over the repair site to a new set of factors. c, Model of the PARP catalytic cycle. Binding and bridging of a DNA break induces conformational changes that activate PARP proteins, enabling HPF1 binding. In the first step, the NAD⁺ channel needs to open to bind NAD⁺. NAD⁺ binding closes NAD⁺ channel, and PARPs can add ADP-ribose to the target residue. After catalytic reaction is completed, the product release channel opens, and product can be released and new substrate can bind. d, Point mutations and cancer-associated single-nucleotide polymorphism variants in PARP1 causing PARP inhibitor resistance are shown as blue sticks.