Elimination of virus-like particles reduces protein aggregation and extends replicative lifespan in Saccharomyces cerevisiae.

A major consequence of aging and stress, in yeast to humans, is an increased accumulation of protein aggregates at distinct sites within the cells. Using genetic screens, immunoelectron microscopy, and three-dimensional modeling in our efforts to elucidate the importance of aggregate annexation, we found that most aggregates in yeast accumulate near the surface of mitochondria. Further, we show that virus-like particles (VLPs), which are part of the retrotransposition cycle of Ty elements, are markedly enriched in these sites of protein aggregation. RNA interference-mediated silencing of Ty expression perturbed aggregate sequestration to mitochondria, reduced overall protein aggregation, mitigated toxicity of a Huntington's disease model, and expanded the replicative lifespan of yeast in a partially Hsp104-dependent manner. The results are in line with recent data demonstrating that VLPs might act as aging factors in mammals, including humans, and extend these findings by linking VLPs to a toxic accumulation of protein aggregates and raising the possibility that they might negatively influence neurological disease progression.

LDL cholesterol level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes mellitus: A nationwide cohort study.

BACKGROUND: Microvascular complications are common in people with diabetes, where poor glycaemic control is the major contributor. The aim of this study was to explore the association between elevated LDL cholesterol levels and the risk of retinopathy or nephropathy in young individuals with type 1 diabetes. METHODS: This was a nationwide observational population-based cohort study, including all children and adults with a duration of type 1 diabetes of ≤ 10 years, identified in the Swedish National Diabetes Register between 1998 and 2017. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) of retinopathy or nephropathy in four LDL cholesterol categories: <2.6 (Reference), 2.6-3.4, 3.4-4.1 and > 4.1 mmol L-1 . RESULTS: In total, 11 024/12 350 (retinopathy/nephropathy, both cohorts, respectively) children and adults (median age 21 years, female 42%) were followed up to 28 years from diagnosis until end of study. Median duration of diabetes when entering the study was 6 and 7 years in the retinopathy and nephropathy cohort, respectively. Median LDL cholesterol was 2.4 mmol L-1 , and median HbA1c level was 61 mmol mol-1 (7.7 %). After multivariable adjustment, the HRs (95% CI) for retinopathy in individuals with LDL cholesterol levels of 2.6-3.4, 3.4-4.1 or > 4.1 mmol L-1 were as follows: 1.13 (1.03-1.23), 1.16 (1.02-1.32) and 1.18 (0.99-1.41), compared with the reference. The corresponding numbers for nephropathy were as follows: 1.15 (0.96-1.32), 1.30 (1.03-1.65) and 1.41 (1.06-1.89). CONCLUSIONS: Young individuals with type 1 diabetes exposed to high LDL cholesterol levels have an increased risk of retinopathy and nephropathy independent of glycaemia and other identified risk factors for vascular complications.

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride.

BACKGROUND: Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease. METHODS: In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS). RESULTS: In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism. CONCLUSIONS: Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted. TRIAL REGISTRATION: NCT01425580.

Earlier intensified insulin treatment of Type 1 diabetes and its association with long-term macrovascular and renal complications.

AIMS: To investigate the incidence of all-cause mortality, composite mortality and morbidity in people with Type 1 diabetes formerly randomized in the Stockholm Diabetes Intervention Study. METHODS: A total of 102 people with Type 1 diabetes were randomized in the period 1982-1984 to intensified conventional treatment or standard treatment with insulin for a mean of 7.5 years. We prospectively re-evaluated this cohort for the period until 2011 with regard to all-cause mortality and composite mortality, which consisted of myocardial infarction, stroke and end-stage renal disease as primary endpoints. Secondary endpoints were first-time hospitalization for myocardial infarction and stroke or end-stage renal disease. Data on HbA1c levels (mean of 22 values/person) were retrospectively collected between 1996 and 2011. RESULTS: During the median follow-up of 28 years, 22 people died: seven in the intensified conventional insulin group compared with 15 in the standard treatment group (P = 0.30). With regard to composite mortality, six people in the intensified conventional insulin group died compared with 11 in the standard treatment group (P = 0.56). For the secondary endpoints, 11 people in the intensified conventional insulin group developed myocardial infarction or stroke compared with 17 in the standard treatment group (P = 0.72), and one person in the intensified conventional insulin compared with seven people in the standard treatment group developed end-stage renal disease (P = 0.09). Mean HbA1c levels did not differ between groups during the follow-up years. CONCLUSIONS: All-cause mortality, cardiovascular morbidity and progression to end-stage renal disease did not differ in people with Type 1 diabetes earlier randomized to intensified insulin treatment.

Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor.

Gliptins are anti-type 2 diabetes (T2D) drugs that regulate glycaemia by preventing endogenous glucagon-like peptide-1 (GLP-1) degradation. Chronically administered gliptins before experimental stroke can also induce neuroprotection, and this effect is potentially relevant for reducing brain damage in patients with T2D and high risk of stroke. It is not known, however, whether acute gliptin treatment after stroke (mimicking a post-hospitalization treatment) is neuroprotective or whether gliptin-mediated neuroprotection occurs via GLP-1-receptor (GLP-1R) activation. To answer these two questions, wild-type and glp-1r(-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO). Linagliptin was administered acutely (50 mg/kg intravenously), at MCAO time or chronically (10 mg/kg orally) for 4 weeks before and 3 weeks after MCAO. Neuroprotection was assessed by stroke volume measurement and quantification of NeuN-positive surviving neurons. Plasma/brain GLP-1 levels and dipeptidyl peptidase-4 activity were also measured. The results show that the linagliptin-mediated neuroprotection against stroke requires chronic pretreatment and does not occur via GLP-1R. The findings provide essential new knowledge with regard to the potential clinical use of gliptins against stroke, as well as a strong impetus to identify gliptin-mediated neuroprotective mechanisms.

Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models.

Ageing of biological systems is accompanied by alterations in mitochondrial morphology, including a transformation from networks and filaments to punctuate units. The significance of these alterations with regard to ageing is not known. Here, we demonstrate that the dynamin-related protein 1 (Dnm1p), a mitochondrial fission protein conserved from yeast to humans, affects ageing in the two model systems we studied, Podospora anserina and Saccharomyces cerevisiae. Deletion of the Dnm1 gene delays the transformation of filamentous to punctuate mitochondria and retards ageing without impairing fitness and fertility typically observed in long-lived mutants. Our data further suggest that reduced mitochondrial fission extends life span by increasing cellular resistance to the induction of apoptosis and links mitochondrial dynamics, apoptosis and life-span control.

Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety.

AIMS/HYPOTHESIS: The aim of this study was to determine whether exenatide improves haemodynamic function in patients with type 2 diabetes with congestive heart failure (CHF). METHODS: The main eligibility criteria for inclusion were: male/female (18-80 years) with type 2 diabetes and CHF (ejection fraction ≤ 35%, and New York Heart Association functional class III or IV). Out of 237 patients screened, 20 male type 2 diabetic patients participated in this crossover trial design and were allocated (sequentially numbered) to i.v. infusions during two consecutive days with (1) exenatide (0.12 pmol/kg/min); and (2) placebo for 6 h followed by a washout period for 18 h, at Stockholm South Hospital, Sweden. Patients and researchers were blinded to the assignment. Cardiac haemodynamic variables were determined by right heart catheterisation. The primary endpoint was defined as an increase in cardiac index (CI) or a decrease in pulmonary capillary wedge pressure (PCWP) of ≥ 20%. Secondary endpoints were tolerability and safety of exenatide infusion. RESULTS: CI increased at 3 and 6 h by 0.4 ± 0.1 (23%) and 0.33 ± 0.1 (17%) l min(-1) m(-2), during exenatide infusion vs -0.02 ± 0.1 (-1%) and -0.08 ± 0.1 (-5%) l min(-1) m(-2) during placebo (p = 0.003); and heart rate (HR) increased at 1, 3 and 6 h by 8 ± 3 (11%), 15 ± 4 (21%) and 21 ± 5 (29%) beats per min (bpm), during exenatide infusion vs -1 ± 2 (-2%), 1 ± 1 (2%) and 6 ± 2 (8%) bpm, during placebo (p = 0.006); and PCWP decreased at 1, 3 and 6 h by -1.3 ± 0.8 (-8%), -1.2 ± 1 (-8%) and -2.2 ± 0.9 (-15%) mmHg, during exenatide infusion vs 0.3 ± 0.5 (2%), 1 ± 0.6 (6%) and 1.4 ± 0.7 (8%) mmHg, during placebo (p = 0.001). No serious adverse event was observed. Adverse events were reported in nine patients (six, nausea; two, increased HR; one, increased systolic blood pressure). CONCLUSIONS/INTERPRETATION: Infusion of exenatide in male type 2 diabetic patients with CHF increased the CI as a result of chronotropy, with concomitant favourable effects on PCWP and reasonable tolerability of the drug. The clinical implications of using exenatide in patients with CHF are still not clear and further studies are warranted. TRIAL REGISTRATION: www.isrctn.org/ISRCTN47533126

Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men.

AIMS: Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest. METHODS: We aimed to investigate longitudinal relationships between plasma levels of fasting GLP-1 (fGLP-1), 60-min oral glucose tolerance test-stimulated GLP-1 levels (60GLP-1), and the dynamic GLP-1 response after oral glucose tolerance test (ΔGLP-1 = 60GLP-1 - fGLP-1) and incidence of hospitalized congestive heart failure, during a follow-up time of a maximum of 9.8 years in 71-year-old men. We also investigated, cross-sectionally, the association between GLP-1 and left ventricular function as estimated by echocardiography. R: During the follow-up period, 16 of 290 participants with normal glucose tolerance experienced a congestive heart failure event (rate 0.7/100 person-years at risk), as did eight of 136 participants (rate 0.8/100 person-years at risk) with impaired glucose tolerance and nine of 72 participants (rate 1.7/100 person-years at risk) with Type 2 diabetes mellitus. Although GLP-1 concentrations did not predict congestive heart failure (fGLP-1: HR 0.98, 95% CI 0.4-2.4; 60GLP-1: HR 1.1, 95% CI 0.4-2.6; ΔGLP-1: HR 0.9, 95% CI 0.3-2.3), there was an association between left ventricular diastolic function (E/A ratio) and fGLP-1 (r = 0.19, P = 0.001), 60GLP-1 (r = 0.20, P < 0.001) and ΔGLP-1 (r = 0.18, P = 0.004). There was a lack of differences in plasma levels of GLP-1 between the groups with Type 2 diabetes and normal glucose tolerance. CONCLUSIONS: There were no longitudinal associations between GLP-1 levels and incidence of hospitalization for congestive heart failure. However, without any causality proven, GLP-1 levels did correlate, cross-sectionally, with left ventricular diastolic function in this cohort, suggesting that pathways including GLP-1 might be involved in the regulation of cardiac diastolic function.

Selective benefits of damage partitioning in unicellular systems and its effects on aging.

Cytokinesis in unicellular organisms sometimes entails a division of labor between cells leading to lineage-specific aging. To investigate the potential benefits of asymmetrical cytokinesis, we created a mathematical model to simulate the robustness and fitness of dividing systems displaying different degrees of damage segregation and size asymmetries. The model suggests that systems dividing asymmetrically (size-wise) or displaying damage segregation can withstand higher degrees of damage before entering clonal senescence. When considering population fitness, a system producing different-sized progeny like budding yeast is predicted to benefit from damage retention only at high damage propagation rates. In contrast, the fitness of a system of equal-sized progeny is enhanced by damage segregation regardless of damage propagation rates, suggesting that damage partitioning may also provide an evolutionary advantage in systems dividing by binary fission. Indeed, by using Schizosaccharomyces pombe as a model, we experimentally demonstrate that damaged proteins are unevenly partitioned during cytokinesis and the damage-enriched sibling suffers from a prolonged generation time and accelerated aging. This damage retention in S. pombe is, like in Saccharomyces cerevisiae, Sir2p- and cytoskeleton-dependent, suggesting this to be an evolutionarily conserved mechanism. We suggest that sibling-specific aging may be a result of the strong selective advantage of damage segregation, which may be more common in nature than previously anticipated.

Reduced plasma levels of glucagon-like peptide-1 in elderly men are associated with impaired glucose tolerance but not with coronary heart disease.

AIMS/HYPOTHESIS: Besides the insulinotropic effects of glucagon-like peptide-1 (GLP-1) mimetics, their effects on endothelial dysfunction and myocardial ischaemia are of interest. No previous study has investigated associations between plasma levels of GLP-1 and CHD. METHODS: We investigated longitudinal relationships of fasting GLP-1 with the dynamic GLP-1 response after OGTT (difference between 60 min OGTT-stimulated and fasting GLP-1 levels [DeltaGLP-1]) and CHD in a population-based cohort of 71-year-old men. In the same cohort, we also cross-sectionally investigated the association between stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus. RESULTS: During the follow-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with DeltaGLP-1, lowest vs highest quartile (OR 0.3, 95% CI 0.12-0.58), with no such association for type 2 diabetes mellitus (OR 1.0, 95% CI 0.38-2.86). M/I was significantly associated with DeltaGLP-1 in the type 2 diabetes mellitus group (r = 0.38, p < 0.01), but not in the IGT (r = 0.11, p = 0.28) or NGT (r = 0.10, p = 0.16) groups. CONCLUSIONS/INTERPRETATION: Impaired GLP-1 secretion is associated with IGT, but not with type 2 diabetes mellitus. This finding in the latter group might be confounded by oral glucose-lowering treatment. GLP-1 does not predict CHD. Although DeltaGLP-1 was associated with insulin sensitivity in the type 2 diabetes mellitus group, GLP-1 does not seem to be a predictor of CHD in insulin-resistant patients.

Starvation, cessation of growth and bacterial aging.

Several components of different Escherichia coli regulons are integrated to prevent premature oxidative deterioration of starving cells. The interconnected regulation of these regulons encompasses oxidation signalling, sigma factor competition, and possibly also the use of sigma factor inhibitors. Recent data demonstrate that stasis-induced oxidation targets both DNA and protein and that some enzymes are specifically susceptible to oxidative attack.

The trials and tribulations of growth arrest.

It is perhaps surprising to learn that many individual genes and global regulatory networks of Escherichia coli are induced as growth of the cells ceases. Insight into the trials and tribulations of the growth-arrested state is being gained from recent data on the regulation of the genes and networks, and on the cellular functions of proteins essential for surviving stasis.

Maintenance energy requirement: what is required for stasis survival of Escherichia coli?

Little is known about how the energy of maintenance is generated in a cell supporting its persistence solely on endogenous carbon material, and what this energy is used for. However, it is clear that the endogenous metabolism of Escherichia coli cells held in the absence of exogenous carbon includes de novo protein synthesis, and that this synthesis is required for the maintenance of the growth-arrested cell. Recent findings suggest that several genes/proteins responding to carbon starvation are themselves involved in reorganizing and modulating catabolic flux, while others form an integral part of a defense system aimed at avoiding the damaging effects of ongoing respiratory activity. A significant fraction of the energy of maintenance is suggested to be required to prevent the denaturation and spontaneous aging of proteins during stasis.

The universal stress protein, UspA, of Escherichia coli is phosphorylated in response to stasis.

Transcriptional induction of the uspA gene of Escherichia coli occurs whenever conditions cause growth arrest and cells deficient in UspA survive poorly in stationary phase. We demonstrate that the product of uspA is a serine and threonine phosphoprotein. In vivo, three isoforms of UspA were detected, two of which were phosphorylated as determined by alkaline phosphatase treatment; in vitro, phosphorylation with [gamma-32P]ATP yielded two radioactive UspA isoforms. The phosphorylated isoforms were barely visible in growing cells but one increased during starvation conditions causing growth arrest. This phosphorylation is dependent on the o591 gene, which encodes an autophosphorylating tyrosine phosphoprotein and which is involved in the synthesis or modification of six other proteins. In vitro, UspA undergoes a rapid and dynamic autophosphorylation, as shown by chase experiments with GTP or ATP as phosphate donors.

Tyrosine phosphorylation in Escherichia coli.

The phosphorylation on tyrosine of a protein in Escherichia coli both in vivo and in vitro was revealed by recognition by anti-phosphotyrosine antibodies, labelling with [gamma-32P]ATP, and phosphoamino acid analysis. This protein, which we name TypA, is the product of the o591 reading frame as revealed by N-terminal sequencing and antibody cross-reactivity. Inactivation of typA altered the patterns of protein synthesis during both exponential growth and carbon starvation. These alterations included the disappearance of an acidic isoform of both the universal stress protein UspA and carbon starvation protein Csp15, and increased synthesis of the histone-like protein H-NS. The sequence of TypA from strain K-12 differs from that of an enteropathogenic strain in six amino acid residues and the protein is three residues shorter. We propose that TypA interacts with global regulatory networks and that its phosphorylation may be relevant to pathogenesis.

In vivo parameters influencing 2-Cys Prx oligomerization: The role of enzyme sulfinylation.

2-Cys Prxs are H2O2-specific antioxidants that become inactivated by enzyme hyperoxidation at elevated H2O2 levels. Although hyperoxidation restricts the antioxidant physiological role of these enzymes, it also allows the enzyme to become an efficient chaperone holdase. The critical molecular event allowing the peroxidase to chaperone switch is thought to be the enzyme assembly into high molecular weight (HMW) structures brought about by enzyme hyperoxidation. How hyperoxidation promotes HMW assembly is not well understood and Prx mutants allowing disentangling its peroxidase and chaperone functions are lacking. To begin addressing the link between enzyme hyperoxidation and HMW structures formation, we have evaluated the in vivo 2-Cys Prxs quaternary structure changes induced by H2O2 by size exclusion chromatography (SEC) on crude lysates, using wild type (Wt) untagged and Myc-tagged S. cerevisiae 2-Cys Prx Tsa1 and derivative Tsa1 mutants or genetic conditions known to inactivate peroxidase or chaperone activity or altering the enzyme sensitivity to hyperoxidation. Our data confirm the strict causative link between H2O2-induced hyperoxidation and HMW formation/stabilization, also raising the question of whether CP hyperoxidation triggers the assembly of HMW structures by the stacking of decamers, which is the prevalent view of the literature, or rather, the stabilization of preassembled stacked decamers.

Effects of starvation for exogenous carbon on functional mRNA stability and rate of peptide chain elongation in Escherichia coli.

The decay rate of the potential to synthesize proteins after complete inhibition of transcription by rifampicin was analyzed to determine the functional mRNA stability of exponentially growing and glucose-starved Escherichia coli B and K12 cells. We found the following: (i) The half-life of the mRNA pool increased 2.2-fold during a period of 2 h of starvation (from 1.8 min in exponentially growing cells to 4.0 min for cells starved for 2 h); (ii) the effect on transcript stability appeared to be global since transcripts of genes that were induced, repressed or unaltered in their expression during starvation exhibited more or less the same increased stability; (iii) the rate of peptide chain elongation, as measured by the synthesis time for beta-galactosidase, decreased 1.9-fold during the starvation period studied and may, at least in part, account for the global stabilization of transcripts in starved cells.

Starvation-induced modulations in binding protein-dependent glucose transport by the marine Vibrio sp. S14.

The uptake kinetics of D-glucose were examined in the marine Vibrio sp. S14 during a period of 168 h of complete energy and nutrient starvation. Two glucose transport systems were distinguished in Vibrio sp. S14: a low affinity system (Km = 4.6 +/- 0.9 microM) at the onset of starvation, and a high affinity system (Km = 0.55 +/- 0.15 microM) after 168 h of starvation. Both systems had a narrow substrate specificity, and both were osmotic shock-sensitive.

Ras proteins control mitochondrial biogenesis and function in Saccharomyces cerevisiae.

The evolutionarily conserved Ras proteins function as a point of convergence for different signaling pathways in eukaryotes and have been implicated in both aging and cancer development. In Saccharomyces cerevisiae the plasma membrane proteins Ras1 and Ras2 are sensing the nutritional status of the environments, e.g., the abundance and quality of available carbon sources. The cAMP-protein kinase A pathway is the most explored signaling pathway controlled by Ras proteins; it affects a large number of genes, some of which are important to defend the cell against oxidative stress. In addition, recent analysis has shown that the Ras system of yeast is involved in the development of mitochondria and in regulating their activity. As a sensor of environmental status and an effector of mitochondrial activity, Ras serves as a Rosetta stone of cellular energy transduction. This review summarizes the physical and functional involvement of Ras proteins and Ras-dependent signaling pathways in mitochondrial function in S. cerevisiae. Since mitochondria produce harmful reactive oxygen species as an inevitable byproduct and are partly under control of Ras, illuminating these regulatory interactions may improve our understanding of both cancer and aging.

UspB, a member of the sigma-S regulon, facilitates RuvC resolvase function.

A growing body of evidence shows that there is an intimate connection between proteins required for genome stability and stationary phase survival. In this work we show that the integral membrane protein UspB, a member of the RpoS regulon, is required for proper DNA repair as mutants lacking uspB are hypersensitive to several DNA damaging agents including ultraviolet light, mitomycin C, bleomycin and ciprofloxacin. Genetic and physical studies demonstrate that UspB acts in the RuvABC recombination repair pathway and removing uspB creates a phenocopy of the Holliday junction resolvase mutant, ruvC. Further, we show that the uspB mutant phenotype can be suppressed by ectopic overproduction of RuvC and that both ruvC and uspB mutants can be suppressed by inactivating recD. The fact that RuvABC-dependent repair requires UspB for proper activity suggests that the sigma-S regulon works together with DNA repair pathways under stress conditions to defend the cell against genotoxic stress.