Abstract <p>DNA repair mechanisms are the main strategies that ensure the preservation of genome integrity during cell life. Defects in repair systems lead to the development of oncological and neurodegenerative diseases, as well as aging. On the other hand, DNA repair activity must be inhibited to increase the effectiveness of DNA-damaging agents used in oncotherapy. A key role in maintaining the optimal status of repair systems is played by regulatory proteins, primarily poly(ADP-ribose) polymerases 1 and 2 (PARP1/2), which participate in the regulation of DNA repair, including by modifying histones during chromatin remodeling. The activity of PARP1 and PARP2, in turn, is regulated by the level of DNA damage, as well as by partner proteins, including RNA-binding proteins containing disordered domains. The most important partner of PARP1/2 is the recently discovered histone poly(ADP-ribosyl)ation (PARylation) factor HPF1, which ensures specificity of protein modification by serine residues and stimulates histone PARylation. The current strategy for developing PARP1/2 inhibitors is aimed at specific regulation of the activity of these enzymes by modulating interactions with partner proteins, which will allow the development of effective and at the same time less toxic therapy for oncological and neurodegenerative diseases.</p>