HPF1 Regulates Pol β Efficiency in Nucleosomes via the Modulation of Total Poly(ADP-Ribose) Synthesis

The maintenance of genome stability and the prevention of genotoxic damage to DNA require immediate DNA repair. In the cell, the repair process is usually preceded by a release of DNA from complexes with chromatin proteins accompanied by nucleosome sliding, relaxing or disassembly. Base excision DNA repair (BER) corrects the most common DNA lesions, which does not disturb the DNA helix dramatically. Notably, small DNA lesions can be repaired in chromatin without global chromatin decompaction. One of the regulatory mechanisms is poly(ADP-ribosyl)ation, leading to the relaxation of the nucleosome. In our work, we demonstrated that recently a discovered protein, HPF1, can modulate the efficiency of one of the key BER stages-DNA synthesis-via the regulation of total poly(ADP-ribosyl)ation. Accordingly, we investigated both short-patch and long-patch DNA synthesis catalyzed by DNA polymerase β (pol β; main polymerase in BER) and showed that HPF1's influence on the poly(ADP-ribosyl)ation catalyzed by PARP1 and especially by PARP2 results in more efficient DNA synthesis in the case of the short-patch BER pathway in nucleosomes. Additionally, HPF1-dependent poly(ADP-ribosyl)ation was found to positively regulate long-patch BER.