DNA replication initiated by one-ended homologous recombination at a double-strand break is highly inaccurate, as it greatly stimulates frameshift mutations over the entire path of the replication fork.
Break-induced replication (BIR) is an important process of DNA metabolism that has been implicated in the restart of collapsed replication forks, as well as in various chromosomal instabilities, including loss of heterozygosity, translocations, and alternative telomere lengthening. Therefore, knowledge of how BIR is carried out and regulated is important for better understanding the maintenance of genomic stability in eukaryotes. Here we present a new yeast experimental system that enables the genetic control of BIR to be investigated. Analysis of mutations selected on the basis of their sensitivity to various DNA-damaging agents demonstrated that deletion of POL32, which encodes a third, nonessential subunit of polymerase d, significantly reduced the efficiency of BIR, although some POL32-independent BIR was still observed. Importantly, the BIR defect in pol32D cells was associated with the formation of half-crossovers. We propose that these half-crossovers resulted from aberrant processing of BIR intermediates. Furthermore, we suggest that the half-crossovers observed in our system are analogous to nonreciprocal translocations (NRTs) described in mammalian tumor cells and, thus, our system could represent an opportunity to further study the NRT mechanism in yeast.
Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2's RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.
Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an anti-angiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogs, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis, and had efficacy in the oxygen-induced retinopathy model in vivo.
Introduction: There is a sex difference in the risk of ischemic acute kidney injury (AKI), and estrogen mediates the protective effect of female sex. We previously demonstrated that preprocedural chronic restoration of physiologic estrogen to ovariectomized female mice ameliorated AKI after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). In the present study, we hypothesized that male mice and aged female mice would benefit from estrogen administration after CA/CPR. We tested the effect of estrogen in a clinically relevant manner by administrating it after CA/CPR. Methods: CA/CPR was performed in young (10-15 weeks), middle-aged (43-48 weeks), and aged (78-87 weeks) C57BL/6 male and female mice. Mice received intravenous 17β-estradiol or vehicle 15 min after resuscitation. Serum chemistries and unbiased stereological assessment of renal injury were completed 24 h after CA. Regional renal cortical blood flow was measured by a laser Doppler, and renal levels of estrogen receptor alpha (ERα) and G protein-coupled estrogen receptor (GPER) were evaluated with immunoblotting. Results: Post-arrest estrogen administration reduced injury in young males without significant changes in renal blood flow (percentage reduction compared with vehicle: serum urea nitrogen, 30 %; serum creatinine (sCr), 41 %; volume of necrotic tubules (VNT), 31 %; P < 0.05). In contrast, estrogen did not affect any outcomes in young females. In aged mice, estrogen significantly reduced sCr (80 %) and VNT (73 %) in males and VNT (51 %) in females. Serum estrogen levels in aged female mice after CA/CPR were the same as levels in male mice. With age, renal ERα was upregulated in females. Conclusions: Estrogen administration after resuscitation from CA ameliorates renal injury in young males and aged mice in both sexes. Because injury was small, young females were not affected. The protective effect of exogenous estrogen may be detectable with loss of endogenous estrogen in aged females and could be mediated by differences in renal ERs. Post-arrest estrogen administration is renoprotective in a sex-and age-dependent manner.
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