Lesions excision

Weng L, Greenberg MM. Rapid histone-catalyzed DNA lesion excision and accompanying protein modification in nucleosomes and nucleosome core particles. J Am Chem Soc. 2015 137 11022-11031. 

If a 1% solution of DNCB is applied on the nipple with acanthosis, there are no lesions (excision 24 hours after application). However if the same solution is applied on a nipple without acanthosis, the usual primary toxic lesions are observed (necrosis of the epidermis). 

Varshney MK, Rastogi S, Khan SA, Trikha V. Is sclerotherapy better than intra-lesional excision for treating aneurysmal bone cysts Clin Orthop Relat Res 2010 468(6) 1649-59. 

Crosslinks result from the reaction of a bifunctional electrophilic species with DNA bases and imply a covalent link between two adjacent DNA strands which inhibits DNA replication. Primary targets within bases are N7 and 06 in guanine and N3 in cytosine. The initial lesions are removed by the suicide enzyme alkyltrans-ferase, whereas nucleotide excision repair is needed for frilly established crosslinks. 

Maccubbin, A., Evans, M., Paul, C.R., Budzinski, E.L., Przybyszewski, J. and Box, H.C. (1991). Enzymatic excision of radiation-induced lesions from DNA model compounds. Radiat. Res. 126, 21-26. 

This work provides important evidence for elucidating the cytotoxic effect of the ruthenium-arene complexes and the influence of the arene thereon, for instance with respect to excision repair of DNA lesions and DNA destabilization. It also established two different classes of Ru(II) arene anticancer drugs, i.e. those bearing an arene that has the possibility to intercalate and those that do not. This distinction is important as we will see further differences in DNA binding interactions for these two classes (vide infra). 

Excision Repair. Some groups of enzymes (light-independent) are apparently organized to act cooperatively to recognize DNA lesions, remove them, and correctly replace the damaged sections of DNA. The most comprehensively studied of these is the excision repair pathway. 

Irritation is evaluated as follows Three rabbits are sacrificed by a lethal dose of barbiturate at approximately 24, 48, or 72-h after dosing. The left and right lateral vastus of each rabbit are excised. The lesions resulting from injection are scored for muscle irritation on a numerical scale of 0 to 5 as follows (Shintani et al., 1967) ... 

DNA base damage is also frequent after radiation (Ward, 1986). As compared to ssb, this DNA lesion is regarded as a possible source of mutation and is repaired through specific DNA repair pathways, such as base excision repair and nucleotide excision repair. 

Utilising a reversion assay in Salmonella enterica, Prieto et al reported an increased frequency of point mutations following bile-salt exposure. Mutations were predominantly nucleotide substitutions (GC to AT transitions) and -1 frameshift mutations.The frameshifts were dependent on SOS induction and linked to the activity of DinB polymerase (Pol IV). The authors proposed that the GC to AT transitions stimulated by bile, could have arisen from oxidative processes giving rise to oxidised cytosine residues. Consistent with this hypothesis, the authors demonstrated that strains of S. enterica-lacking enzymes required for base-excision repair (endonuclease III and exonuclease IV) and the removal of oxidised bases, demonstrated increased bile-acid sensitivity compared with competent strains. In another study using E. coli, resistance to the DNA-damaging effects of bile was associated with Dam-directed mismatch repair, a pathway also involved with the repair of oxidative DNA lesions. ... 

The rate of resectability is only 15-20% for proximal bile duct carcinomas but up to 70% for distal lesions. In addition, there is little benefit to preoperative decompression of the biliary tree in patients having obstructive jaundice (65,66). However, this procedure is frequently practiced. For proximal cancers, local excision is often possible. In particular, hepatic resection is indicated for upper bile duct cancers with quadrate lobe invasion or unilateral intrahepatic ductal or vascular involvement, and distal and midductal lesions may require pancreatoduodenectomy. Also, biliary-enteric continuity... 

Figure 19.5 Visualization of DNA damage induction in cultured human keratinocytes by photo-activated lomefloxacin using the comet assay. The presence of DNA breaks (induced either by ROS or by excision of DNA lesions) leads to fragmentation and electrophoretic migration to produce the comet tails, whereas bulky genomic DNA remains in the comets heads.

Nucleotide excision repair involves the removal of the region surrounding a modified base or single-strand break by nuclease-mediated excision (cutting) of the DNA strand on either side of the lesion followed by filling of the resulting gap. 

Simple experimental approaches to this problem recently started postulate that the repair of clustered DNA damage leads to conversion of nonlethal lesions, e.g., dihydrothymine, or mutagenic lesions, such as 8-OxoGuanine, into lethal double strand breaks. These early experiments have studied kinetics and influence of excision of base lesion within clustered DNA damage by E. coli and nuclear extracts [27,123-129]. 

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