Lesion bypass

The bacterial protein LexA has been identified as playing a key role in the acquisition of bacterial mutations. Repressor LexA represses SOS response genes that code for those DNA-polymerases required for repairing DNA damage. The SOS response is a post-replication DNA-repair system that allows DNA replication to bypass lesions or errors in the DNA. 

The DNA polymerase II (pol 11) is the most known bacterial B-family polymerase. It is coded by polB gene and has 3 -5 exonuclease activity [14], Pol II participates in the DNA repair and replication restart to bypass lesions. Its ceU presence can vary from 30 to 50 copies per cell to 200-300 dtrring SOS induction. Pol II is also thought to be a backup to pol 111 as it can interact with holoenzyme proteins and assumes a high level of processivity. The special role of pol 11 is thought to be the ability to direct polymerase activity at the replication fork and its help to the staUed pol 111 in bypassing terminal mismatches [14]. 

Evans, J., Maccabee, M., Hatahet, Z., Courcelle, H., Bockrath, R., Ide, H. and Wallace, S. (1993). Thymine ring saturation and fragmentation products, lesion bypass, misinsertion and implications for mutagenesis. Mut. Res. 299, 147-156. 

The accumulation of apo(a) in the aorta wall and in saphenous vein bypass grafts in relation to Lp(a) levels was recently demonstrated (C14, R3). Subsequently, the preferential deposition of extracellular apo(a) in atherosclerotic lesions of aortic and coronary artery tissue, in conjunction with the intracellular localization of apo(a) in macrophage-derived foam cells, has been the focus of a number of studies (N6, P7, S34, S35, W17). These careful studies also demonstrated the avid binding of Lp(a) to extracellular matrix components and the colocalization of fibrin and apo(a) in atheromatous lesions (N8, W16). 

In mammalian cells, at least eight DNA polymerases are present. DNA polymerase a is involved in the initiation of DNA synthesis at DNA replication origins and lagging strand synthesis (Wang, 1991). DNA polymerase 7is a mitochondrial DNA polymerase (Wang, 1991). Recently, bypass polymerases, such as DNA polymerase V, t. and Chave also been identified (Lindahl and Wood, 1999). These DNA polymerases are capable of continuing DNA synthesis even through bulky DNA lesions—such as UV-induced pyrimidine-dimers in the template strand (Lindahl and Wood, 1999). 

Boudsocq, F., Iwai, S., Hanaoka, F., and Woodgate, R. (2001). Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) An archaeal DNA polymerase with lesion-bypass properties akin to eukaryotic pol q. Nucleic Acids Res. 15, 4607-4613. 

Ling, H., Boudsocq, F., Woodgate, R., and Yang, W. (2001). Crystal structure of a Y-Family DNA polymerase in action A mechanism for error-prone and lesion-bypass replication. Cell 107, 91-102. 

Zhou, B. L., Pata, J. D., and Steitz, T. A. (2001). Crystal structure of a DinB lesion bypass DNA polymerase catalytic fragment reveals a classic polymerase catalytic domain. Mol. CellS, 427-437. 

CHD = myocardial infarction (Ml), significant myocardial ischemia (angina), history of coronary artery bypass graft (CABG), history of coronary angioplasty, angiographic evidence of lesions, carotid endarterectomy, abdominal aortic aneurysm, peripharal vascular disease (claudication), thrombotic/embolic stroke, transient ischemic attack (TIA)... 

Inclusion criteria were similar to our previous pilot study (34), Patients with clinical indication of percutaneous coronary revascularization were randomized if they had a de novo severe stenosis in a native coronary artery, a lesion suitable for stent, and a reference vessel size between 2.5 and 4.0 by visual estimation, and were a candidate for coronary bypass surgery, All the PCI procedures were performed at the Catheterization Laboratories at Otamendi Hospital and Sanatorio Las Lomas in Buenos Aires, Argentina. 

Abbreviations BRILLIANT-EU, Batimastat (BB94) anti-restenosis trial utilizing the BiodivYsio local drug delivery PC-stent CABG, coronary artery bypass graft MACE, major adverse cardiac events Ml. myocardial infarction TLR, target lesion revascularization. 

Patient presents with acute lower extremity ischemia, thrombotic lesion in common femoral artery with femoropopliteal bypass occlusion. 

Fig. 4. Possible role of mismatch repair in the cytotoxicity of cisplatin. A) During replicative bypass, a mismatch is incorporated across from the cisplatin-DNA adduct. This compound lesion is bound by the mismatch repair proteins, which cut the DNA on the strand opposite the platinum. Repair synthesis would reproduce the same mismatch, resulting in a futile cycle and possibly the accumulation of DNA strand breaks which would activate apoptosis. B) Alternatively, the mismatch repair complex can recognize the cisplatin-DNA adduct alone and generate a signal that triggers apoptosis.

Accordingly, some effort has been devoted to studying the effects of cisplatin on transcription. In vitro experiments with RNA polymerases demonstrated that productive elongation activity was prematurely terminated by the whole spectrum of cisplatin-DNA adducts, but not by the /ran.y-DDP 1,3-intrastrand adducts [150-152], Selective bypass of trans-DDP adducts was also demonstrated in XPA cells, suggesting that repair of the DNA lesions did not contribute to differential transcription inhibition by the platinum compounds [153], In vivo, hormone-induced chromatin remodeling and subsequent transcription from the MMTV promoter was specifically inhibited by cisplatin [154], In this case, platinum adducts seemed to cause a decrease in the DNA binding of one of the transcription factors, NF1. Several chromatin-associated proteins, such as the linker histone protein HI or... 

---