Silicone breast implants have been in use for nearly 6 decades. In this time they have undergone significant changes in design and use. They have been subject to intense scrutiny with regard to safety and efficacy, including an almost 10 years moratorium on their use. The current generations of implants have been followed via the manufacturer's Core studies in order to obtain long term data regarding safety and complications. The results of the more recent studies are compiled in this review. Rupture rates are initially very low and begin to increase after 6-8 years of implantation. Implant rupture may be detected by physical exam, ultrasound or magnetic resonance imaging (MRI). The majority of silicone implant ruptures are clinically undetectable. Symptomatic patients may present with capsular contracture, breast lumps or changes in breast shape. The most common cause of implant rupture is instrument damage during placement. Implant rupture may be confined to the peri-prosthetic capsule or may extravasate into the breast tissue. Patients with ruptured implants have been studied closely and the consensus of the literature states there are no health risks associated with implant rupture. Symptomatic patients with ruptured implants should be offered the choice of observation, or explantation and capsulectomy with or without replacement.

1-Nitropyrene, the most abundant nitro polycyclic aromatic hydrocarbon in diesel emissions, has been found to react with DNA to form predominantly N-(deoxyguanosin-8-yl)-1-aminopyrene (dG AP ). This bulky adduct has been shown to induce genetic mutations, which may implicate Y-family DNA polymerases in its bypass in vivo. To establish a kinetic mechanism for the bypass of such a prototype single-base lesion, we employed pre-steady-state kinetic methods to investigate individual nucleotide incorporations upstream, opposite, and downstream from a site-specifically placed dG AP lesion catalyzed by Sulfolobus solfataricus DNA polymerase IV (Dpo4), a model Y-family DNA polymerase. Dpo4 was able to bypass dG AP but paused strongly at two sites: opposite the lesion and immediately downstream from the lesion. Both nucleotide incorporation efficiency and fidelity decreased significantly at the pause sites, especially during extension of the bypass product. Interestingly, a 4-fold tighter binding affinity of damaged DNA to Dpo4 promoted catalysis through putative interactions between the active site residues of Dpo4 and 1-aminopyrene moiety at the first pause site. In the presence of a DNA trap, the kinetics of nucleotide incorporation at these sites was biphasic in which a small, fast phase preceded a larger, slow phase. In contrast, only a large, fast phase was observed during nucleotide incorporation at non-pause sites. Our kinetic studies support a general kinetic mechanism for lesion bypass catalyzed by numerous DNA polymerases.Environmental pollutants have been shown to impact human health at the molecular level. One detrimental route is the modification of genomic DNA and nucleotides (1). If DNA lesions are not recognized and removed by the cellular DNA repair machinery, they will stall replicative DNA polymerases (2-8).To rescue DNA replication, cells employ lesion bypass DNA polymerases to traverse unrepaired lesions. Most of these enzymes belong to the Y-family of DNA polymerases. The Y-family enzymes possess relatively flexible and solvent-accessible active sites to accommodate bulky DNA lesions (9, 10). However, Y-family DNA polymerases catalyze DNA synthesis over undamaged DNA with low fidelity and poor processivity (6, 10 -12). The Y-family DNA polymerases have been identified in all three domains of life, e.g. four in humans (DNA polymerases , , , and Rev1), two in Escherichia coli (DNA polymerases IV and V), and one in Sulfolobus solfataricus (Dpo4). Because Dpo4 can be expressed in E. coli and purified with a high yield, it has been extensively studied in vitro as a prototype Y-family enzyme. Dpo4 catalyzes DNA synthesis on an undamaged DNA template with a fidelity of one error per 1,000 -10,000 nucleotide incorporations based on presteady-state kinetic analysis from 37 to 56°C (13-15). Dpo4 is capable of bypassing a myriad of DNA lesions including apurinic/apyrimidinic (abasic) sites (16 -19), 8-oxo-7,8-dihydro-2Ј-deoxyguanosine (20, 21), 1,N 2 -etheno(⑀)guanosine (22), cis-syn thymine-thymine dimer (23-...

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During DNA synthesis, most DNA polymerases and reverse transcriptases select against ribonucleotides via a steric clash between the ribose 2′-hydroxyl group and the bulky side chain of an active site residue. Here, we demonstrated that human DNA polymerase λ used a novel sugar selection mechanism to discriminate against ribonucleotides, whereby the ribose 2′-hydroxyl group was excluded mostly by a backbone segment and slightly by the side chain of Y505. Such a steric clash was further demonstrated to be dependent on the size and orientation of the substituent covalently attached at the ribonucleotide C2′ position.

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