Urethral Steinstrasse following Laser Lithotripsy of Prostatic Urethral Calculi

Symptomatic prostatic calculi are rare occurrences with several management options, the most popular of which is currently transurethral laser lithotripsy. This is a generally well-tolerated procedure with minimal complications. To date, no reported episodes of steinstrasse at the urethral level following prostatic calculi lithotripsy have been documented to our knowledge. We report a unique case of acute urinary retention secondary to obstructive calculi fragments following a transurethral laser lithotripsy of large prostatic calculi, further complicated by stricture at the fossa navicularis

Early Stone Manipulation in Urinary Tract Infection Associated with Obstructing Nephrolithiasis

A urinary tract infection (UTI) and sepsis secondary to an obstructing stone are one of the few true urological emergencies. The accepted management of infected ureteral stones includes emergent decompression of the collecting system as well as antibiotic therapy. Despite this, no consensus guidelines clarify the optimal time to undergo definitive stone management following decompression. Historically, our institution has performed ureteroscopy with laser lithotripsy (URS-LL) treatment at least 1 to 2 weeks after decompression to allow for clinical improvement and completion of an antibiotic course. In this case series, we retrospectively review four cases in which patients had a documented UTI secondary to an obstructive ureteral stone. The patients underwent urgent decompression and, based on labs and clinical improvement, were subsequently treated with URS-LL. The presented patients received URS-LL within 5 days of decompression and antibiotics. The patients had no sepsis related postoperative complications from the accelerated course of treatment, resulting in discharge within 2 days following URS-LL. We provide a detailed examination of each patient presentation to describe our institution’s experience with treating infected kidney stones within days of urgent decompression in order to question the previous standard of treating an infected kidney stone with a more delayed intervention

Molecular Chaperone Hsp90 Regulates REV1-Mediated Mutagenesis▿

REV1 is a Y-family polymerase that plays a central role in mutagenic translesion DNA synthesis (TLS), contributing to tumor initiation and progression. In a current model, a monoubiquitinated form of the replication accessory protein, proliferating cell nuclear antigen (PCNA), serves as a platform to recruit REV1 to damaged sites on the DNA template. Emerging evidence indicates that posttranslational mechanisms regulate REV1 in yeast; however, the regulation of REV1 in higher eukaryotes is poorly understood. Here we show that the molecular chaperone Hsp90 is a critical regulator of REV1 in human cells. Hsp90 specifically binds REV1 in vivo and in vitro. Treatment with a specific inhibitor of Hsp90 reduces REV1 protein levels in several cell types through proteasomal degradation. This is associated with suppression of UV-induced mutagenesis. Furthermore, Hsp90 inhibition disrupts the interaction between REV1 and monoubiquitinated PCNA and suppresses UV-induced focus formation. These results indicate that Hsp90 promotes folding of REV1 into a stable and/or functional form(s) to bind to monoubiquitinated PCNA. The present findings reveal a novel role of Hsp90 in the regulation of TLS-mediated mutagenesis

NMR Structure and Dynamics of the C-Terminal Domain from Human Rev1 and Its Complex with Rev1 Interacting Region of DNA Polymerase η

Rev1 is a translesion synthesis (TLS) DNA polymerase essential for DNA damage tolerance in eukaryotes. In the process of TLS stalled high-fidelity replicative DNA polymerases are temporarily replaced by specialized TLS enzymes that can bypass sites of DNA damage (lesions), thus allowing replication to continue or postreplicational gaps to be filled. Despite its limited catalytic activity, human Rev1 plays a key role in TLS by serving as a scaffold that provides an access of Y-family TLS polymerases polη, ι, and κ to their cognate DNA lesions and facilitates their subsequent exchange to polζ that extends the distorted DNA primer–template. Rev1 interaction with the other major human TLS polymerases, polη, ι, κ, and the regulatory subunit Rev7 of polζ, is mediated by Rev1 C-terminal domain (Rev1-CT). We used NMR spectroscopy to determine the spatial structure of the Rev1-CT domain (residues 1157–1251) and its complex with Rev1 interacting region (RIR) from polη (residues 524–539). The domain forms a four-helix bundle with a well-structured N-terminal β-hairpin docking against helices 1 and 2, creating a binding pocket for the two conserved Phe residues of the RIR motif that upon binding folds into an α-helix. NMR spin-relaxation and NMR relaxation dispersion measurements suggest that free Rev1-CT and Rev1-CT/polη-RIR complex exhibit μs-ms conformational dynamics encompassing the RIR binding site, which might facilitate selection of the molecular configuration optimal for binding. These results offer new insights into the control of TLS in human cells by providing a structural basis for understanding the recognition of the Rev1-CT by Y-family DNA polymerases.National Institute of Environmental Health Sciences (ES015818)Massachusetts Institute of Technology. Center for Environmental Health Sciences (Grant P30 ES002109