Prdx5 regulates DNA damage response through autophagy-dependent Sirt2-p53 axis.

DNA damage response (DDR) is an important signaling-transduction network that promotes the repair of DNA lesions which can induce and/or support diseases. However, the mechanisms involved in its regulation are not fully understood. Recent studies suggest that the peroxiredoxin 5 (Prdx5) enzyme, which detoxifies reactive oxygen species, is associated to genomic instability and signal transduction. Its role in the regulation of DDR, however, is not well characterized. In this study, we demonstrate a role of Prdx5 in the regulation of the DDR signaling pathway. Knockdown of Prdx5 resulted in DNA damage manifested by the induction of phosphorylated histone H2AX (γ-H2AX) and p53-binding protein 1 (53BP1). We show that Prdx5 regulates DDR through (1) polo-like kinase 1 (Plk1) mediated phosphorylation of ataxia telangiectasia mutated (ATM) kinase to further trigger downstream mediators Chek1 and Chek2; (2) the increase of the acetylation of p53 at lysine 382, stabilizing p53 in the nucleus and enhancing transcription and (3) the induction of autophagy, which regulates the recycling of molecules involved in DDR. We identified Sirt2 as a novel deacetylase of p53 at lysine 382, and Sirt2 regulated the acetylation status of p53 at lysine 382 in a Prdx5-dependent manner. Furthermore, we found that exogenous expression of Prdx5 decreased DNA damage and the activation of ATM in Pkd1 mutant renal epithelial cells, suggesting that Prdx5 may play a protective role from DNA damage in cystic renal epithelial cells. This study identified a novel mechanism of Prdx5 in the regulation of DDR through the ATM/p53/Sirt2 signaling cascade.

Improving Intrapartum Group B Streptococcus Prophylaxis in Patients with a Reported Penicillin or Cephalosporin Allergy: A Quality Improvement Project.

OBJECTIVE: To evaluate the impact of a standardized allergy-guided approach to Group B Streptococcus (GBS) prophylaxis in pregnant women with reported penicillin or cephalosporin allergy. METHODS: This interrupted time-series analysis included obstetric patients requiring GBS prophylaxis who reported penicillin or cephalosporin allergies. Patients were divided into baseline (April 1, 2019 to July 21, 2020) and intervention (July 22, 2020 to July 31, 2021) groups. The primary outcome was prophylaxis appropriateness, based on antibiotic type, nature of reaction, and cross-reactivity risk. Secondary outcomes included type of prophylaxis received and antibiotic-related adverse events. RESULTS: The study included 88 patients in the baseline period and 52 patients in the intervention period. Appropriate prophylaxis increased from 47% (41/88) to 85% (44/52), with the segmented regression model confirming a statistically significant increase over time (incidence rate ratio 1.57; 95% CI 1.02-2.43, P = 0.04, slope coefficient 1.06/month; 95% CI 1.01-1.10, P = 0.01). Penicillin and cefazolin use increased from 61% (54/88) to 87% (45/52) in the intervention period (P = 0.002), and no hypersensitivity reactions occurred during this period. CONCLUSIONS: Implementation of standardized allergy-guided prophylaxis safely improved appropriate ß-lactam antibiotic use in obstetric patients requiring GBS prophylaxis who reported penicillin and cephalosporin allergies.