## 6 Global Genome Repair (GGR)
### Discrimination of Native DNA from Damaged by UvrA
Although the main contours of damage discrimination during NER have been described, there are indications that either the standard model is incomplete or that there are species-specific mechanisms. The finding that alkylated DNA damage, which is ordinarily repaired by direct reversal [103; 104] or base excision repair [105], can also be repaired by NER with the help of alkyltransferase-like proteins (ATLs) [106], suggests that collaborations with other proteins may be a little understood feature of UvrA. Studies show that the ATL protein contacts both UvrA and UvrC [107]. In addition, UvrA binds to oligomeric ATL on both damaged and undamaged DNA and the resulting complex translocates on theDNA duplex [108]. The finding that _E. coli_ and _Bacillus caldotenax_UvrB\(\bullet\)UvrC complex can perform NER in the absence of UvrA [109], that _Mycobacterium tuberculosis_UvrA and UvrC may directly interact [110] and that UvrA, UvrB and UvrC can form a complex termed the repaiosome [109; 111], each challenges the standard model; these observations imply that additional chapters of the NER story remain to be uncovered. The precise molecular signature in damaged DNA that enables its discrimination from native DNA, along with structural changes experienced by UvrA during GGR, remains to be described. However, structural and biochemical analyses have primed several hypotheses that provide a framework for understanding both features [19; 20; 21; 22]. The crystal structure of UvrA bound to a symmetric DNA duplex with a lesion on both strands suggested indirect readout of the presence of damage. Inspection of the structure, along with structure-function studies lay the foundation for understanding two properties of the UvrA\(\bullet\)DNA complex: non-specific interactions that would be required for genome scanning and structural changes associated with formation of a tight complex on damaged DNA. The signature domain II and the insertion domain contribute the majority of contacts to DNA [19; 21], as anticipated [37; 43]. In addition, it is now clear that one locus of damage-specific contacts is the \(\beta\)-hairpin/Zn-binding module (Zn3 hp) element; inserted into the ABC signature domain II. This structural element is unique to UvrA and is coupled to nucleotide dynamics at the proximal site [41]. The position of this element is altered upon binding DNA [19]. Furthermore, compromising the integrity of this element by deletion of the Zn-binding module [42; 43; 109] or restricting its motion by cross-linking [41] impairs the capacity to discriminate damaged from native DNA. The data above have led to two proposed frameworks for understanding discrimination between native and damaged DNA by UvrA. The first suggests that UvrA may subject DNA to a'stress test' by coupling ATP binding and hydrolysis to unwinding, stretching and compressing DNA [22]. Damaged DNA, which is known to harbor non-native base stacking [85], is more likely to bend and buckle, leading to strand separation [85]; damaged DNA fails this test and is passed to the damage specific steps of NER [22]. A second model arose from study of the two dimer configurations ('open tray' and 'closed groove', below) of UvrA; it was suggested that these two configurations subject DNA to a shape test: natively shaped DNA passes the test, while aberrantly shaped lesion-containing DNA fails and is shunted towards the damage specific stages of NER [21]. Notably, the two hypotheses are not mutually exclusive and the actual mechanism may blend elements of both models.