## 2 The UvrA DNA Damage Sensor  
During GGR, the UvrA protein operates as the first responder to lesions in the genome. UvrA is a tandem ABC (ATP binding cassette) ATPase [31; 32] with a dimeric molecular weight of over 200 kDa. ABC proteins comprise a large family that use the energy of ATP binding and hydrolysis to perform work in the cell, most of which is associated with transport across cellular membranes. UvrA is, however, one of the few ABC ATPases that performs transactions with nucleic acids [33; 34]. Conserved among ABC proteins is a 250-amino acid nucleotide binding domain (NBD), with a number of sequence/structural motifs, namely the Walker A/P loop, the Q loop, the ABC signature motif, the Walker B sequence, the D loop and the H loop/switch [35; 36]. In a typical ABC protein, two protein chains each contribute an NBD to the complete dimeric entity. The physiological ensemble features two composite ABC-style nucleotide binding sites; the ATP binding domain (Walker A/P loop, Q loop, Walker B, D loop and H loop/switch) from one chain partners with the ABC signature (SIG) of the second and vice versa. UvrA exhibits features of a typical ABC protein but also harbors several unique elaborations. First, the two NBDs (termed NBD-I and NBD-II) that comprise a functional ABC ATPase unit are found on the same protein chain. Second, the active entity of UvrA is a dimer and thus features a total of four nucleotide binding sites. The nucleotide binding sites are designated as proximal and distal based on their relationship to the dimer interface [37]. The proximal site has been implicated in the interactions of UvrA with UvrB and DNA [21; 38], whereas the distal site has been reported to play a key role in the discrimination of native from damagedDNA [21; 39; 40; 41]. Third, the UvrA protein encompasses a number of unique elements not found in any other ABC protein, namely the UvrB binding domain, three zinc modules (Zn1, Zn2 and Zn3), a hairpin element connected to the Zn3 module (Zn3 hp) and the insertion domain (ID). Among these unique elements, the Zn3 hp and the insertion domain participate in contacts with DNA [19; 42; 43; 44]. Currently, there are eight UvrA structural models from four bacterial species (PDB IDs = 2R6F, 2 VF7, 2 VF8, 3 PHH, 3 UWX, 3 UX8, 3 ZQJ, 6N9L). The models populate two dimeric configurations [19; 21; 37; 44; 45; 46]; considerable similarity in conformation is found in the ABC NBD portion of each protein, while the unique elements occupy divergent relative positions (Figure 2A). Figure 2: Architecture of nucleotide excision repair proteins. (**A**) Structure of _Thermotoga maritima (Tma)_UvrA dimer bound to lesion-containing duplex DNA (PDB: 3 PHH) [19], with \(\alpha\)-helices depicted as cylinders and \(\beta\)-strands as arrows. One protomer is colored by domains, whereas the other is shown in gray. The Zn atoms are shown in light green; the bound ADP molecules are shown as space-filling models. The dimer was generated by application of a crystallographic two-fold axis to the contents of the crystallographic asymmetric unit, which contains one molecule of UvrA and one strand of DNA. The location of each protein domain is projected onto the primary sequence of _Tma_UvrA, shown as a bar. (**B**) Structure of _Bacillus calbotanx (Baa)_UvrB tethered to duplex DNA via disulfide crosslinking (PDB: 60 SE) [47]. The protein is colored by domains; the bound ADP molecule is shown using space-filling model. The location of each protein domain is projected onto the primary sequence of _Bca_UvrB, shown as a bar. (**C**) Structures of _Thermotoga maritima (Tma)_UvrC catalytic domains and DNA-binding domain. The GIV-YIG catalytic domain for 3\({}^{\prime}\) incision (PDB: 1Y1D) [48] and the RNase H-like catalytic domain for 5\({}^{\prime}\) incision (PDB: 2 NRZ) [49] are shown in cyan and yellow, respectively.