**4. Interactions of BER proteins with noncanonical factors contribute to the regulation of DNA repair**

 Many proteins with various cellular functions, not considered previously to be involved in BER, have been shown to regulate this process via interactions with main participants. The HMGB1 protein—a chromatin architecture factor—interacts directly with three BER enzymes (APE1, Polβ, and FEN1), modulates their catalytic activity in the process of DNA repair, and, hence, ensures regulation of the process via the SP or LP BER sub-pathway [79–81]. Human DNA-binding proteins hSSB1 and SATB1 form complexes with DNA glycosylase OGG1, thus enhancing its efficiency in recognition of DNA damage and its repair [82, 83]. The human mitochondrial single-stranded DNA binding protein (mtSSB) interacts with NEIL1 in the presence and absence of a DNA substrate revealed to modulate the oligomerization state and stability of the NEIL1-mtSSB complex [84]. Protein factors of unknown nature that are not involved in chromatin structure remodeling form complex with DNA glycosylase NTH1 and stimulate its activity in BER initiation [85]. The SSRP1 protein entailed in chromatin disassembly as a histone H2A/H2B chaperone interacts with both PAR-PARP1 and XRCC1 and facilitates repair of SSBs [86]. In general, the mechanisms of BER functioning within chromatin are largely unexplored (for example, see [87]), remaining possibility to discover new noncanonical factors of BER.

In addition to multiple enzymatic functions in DNA repair, APE1 is known to play a regulatory role in the transcription processes, RNA processing, and ribosome biogenesis [76, 88]. The activities of the multifunctional enzyme, its expression level, and intracellular localization are regulated by its interaction with the multifunctional protein nucleophosmin (NPM1) [89]. Direct interactions of APE1 and several DNA glycosylases (TDG, NEIL2, NTH1, OGG1, and UNG2) with protein factors of nucleotide excision repair (XPC, XPG, CSB, and RPA) and homologous recombination (Rad52) have been shown to play a regulatory role in the overlapping repair pathways [90].

 PARP1 forms stable complexes with Ku70/Ku80 proteins, and this interaction has been proposed to be an important regulator of the Ku70/80 heterodimer function in the repair of DNA double-strand breaks (DSBs) [91, 92]. Recent studies have demonstrated the involvement of Ku70 and Ku80 proteins in different steps of BER [93]. Septin4, a member of GTP binding protein family considered to be an essential component of the cytoskeleton, is a novel PARP1 interacting protein, and the interaction is enhanced under oxidative stress [94]. PARP1 interacts with NR1D1 protein, a nuclear receptor subfamily 1 group D member 1; the interaction is enhanced under oxidative stress and inhibits the catalytic activity of PARP1 [95]. Whether the interaction of these noncanonical factors with PARP1 may contribute to regulation of BER remains to be explored. The protein DBC1 (deleted in breast cancer 1), one of the most abundant yet enigmatic proteins in mammals containing a conserved domain similar to Nudix hydrolases (hydrolyzing nucleoside diphosphates) but lacking catalytic activity, interacts directly with the BRCT domain of PARP1; the strength of the interaction shown to inhibit the catalytic activity of PARP1 is modulated by NAD+ concentration [96]. Thus, a novel function of NAD+ to directly regulate proteinprotein interactions, the modulation of which may protect against cancer, radiation, and aging, has been discovered.

The multifunctional Y-box-binding protein 1 (YB-1) is another noncanonical factor of BER. The proteolytic fragment of this positively charged intrinsically disordered protein localized in the nucleus is formed in response to DNA damage [97]. We have shown that YB-1 interacts with poly(ADP-ribose) and could be an acceptor for PARP1/PARP2 catalyzed poly(ADP-ribosyl)ation *in vitro* [98]. Several proteins essential for BER—APE1, Polβ, NEIL1, PARP1, and PARP2—directly interact with YB-1, although most complexes being less stable than the complexes of BER proteins with each other (the apparent Kd values are in the range of 340 to 810 nM as compared to those presented in **Figure 4**) [99]. A strong interaction detected between APE1 and YB-1 could be an important factor for the cooperative action of these multifunctional proteins in transcription regulation [100]. Interactions of YB-1 protein with BER enzymes could be responsible for the regulation of their activities: the AP-endonuclease activity of APE1 and 5′-dRp-lyase activity of Polβ are inhibited in the presence of YB-1, while the AP-lyase activity of NEIL1 is stimulated [99]. YB-1 was found to stimulate the catalytic activity of PARP1 via strong binding with poly(ADP-ribose) linked to PARP1, which increased the lifetime of this complex in DNA [99]. Acting as a cofactor of PARP1, YB-1 decreases the efficiency of PARP1 inhibitors [101].
