**1. Introduction: Base Excision Repair**

DNA in living cells is always exposed to many damaging factors of environmental and endogenous origin. These insults produce various modifications of nucleobases and lead to the formation of apurinic/apyrimidinic (AP) sites and DNA strand breaks. Accumulating damage significantly affects genomic stability and may ultimately end in mutations or cell death [1,2].

Mechanisms that correct genomic damage, commonly known as DNA repair systems, exist in all forms of life [1]. The most abundant DNA lesions—deaminated, oxidized, and alkylated bases, AP sites, single-strand breaks—are repaired by the base excision repair (BER) system [1,3]. Initially, the damaged base is recognized by a DNA glycosylase (of which, 11 are known in humans, and 8 in *Escherichia coli*), which cleaves the *N*-glycosidic bond between the nucleobase and the C10 deoxyribose atom, forming an AP site. Afterwards, an AP endonuclease hydrolyzes the phosphodiester bond 50 to the AP site. The repair proceeds with the incorporation of the correct dNMP by a DNA polymerase and the ligation of the remaining single-strand break (Figure 1).

DNA glycosylases belong to several major structural superfamilies and have different, sometimes overlapping, substrate specificities (Table 1). They all, however, have a common reaction mechanism: the C10 of the damaged nucleotide is attacked by a nucleophilic moiety (either an activated water molecule in monofunctional DNA glycosylases or an enzyme's amino group in bifunctional ones), the damaged base departs, and either an AP site is generated (monofunctional glycosylases), or a Schiff base covalent intermediate forms (bifunctional glycosylases) [4–6]. The Schiff base undergoes β- or β,δ-elimination and is then hydrolyzed, leaving a nick with either an α,β-unsaturated aldehyde or a phosphate as the 30 -terminal group. To access C10 , most glycosylases flip the target nucleotide from the DNA stack into the enzyme's active site, which is equipped with a deep lesion recognition pocket, representing a convenient druggable target [7].

**Figure 1.** General base excision repair (BER) scheme. Bases are represented by shaded squares, and sugars by white squares. A damaged base (black) is excised by a DNA glycosylase (1); the resulting apurinic/apyrimidinic (AP) site is cut by an AP endonuclease (2); the deoxyribose fragment is removed by a deoxyribophosphate lyase (3); a correct dNMP is incorporated by a DNA polymerase, and the nick is sealed by a DNA ligase (4). Nicked DNA also activates signaling by poly(ADP-ribose)polymerase 1 (PARP1), which initiates poly(ADP-ribosyl)ation of many chromatin proteins to facilitate the access of DNA repair factors to the site of damage.


**Table 1.** Examples of DNA glycosylases found in humans, *Escherichia coli*, and other species.

In human cells, BER is tightly regulated at several levels. One of the best-studied players orchestrating the BER process is poly(ADP-ribose)polymerase 1 (PARP1), together with its homologs PARP2 and PARP3, which act as nick sensors and regulate the access of repair factors to the damage sites through modification of acceptor proteins and DNA ends by poly(ADP-ribose) [8,9]. PARPs attracted attention as potential targets for cancer treatment after PARP inhibitors were discovered to be highly toxic for cells with inactivated homologous recombination repair pathway [10,11]. In human tumors, recombination repair deficiency is often associated with inactivating mutations in the *BRCA1* and *BRCA2* genes, the main driver mutations in hereditary breast and ovarian cancers. BRCA1 and BRCA2 proteins regulate the DNA break response through a pathway that does not overlap with BER [12]. Blocking both these pathways is lethal for the cell, while normal cells with active recombination repair survive PARP1 inhibition. The lethal effect of PARP inhibitors is largely mediated by PARP trapping at nicks [13,14], which mainly originate from ribonucleotides misincorporated during DNA replication [15]. Several PARP inhibitors are presently approved for clinical use, and several hundred clinical trials are ongoing.
